bims-kishpe 2024-12-01 papers

bims-kishpe

Biomed News

on HSP70 role in hypoxia and metabolism in ECs

Issue of 2024–12–01
27 papers selected by
Alia Ablieh, Universität Heidelberg

Metabolic alterations of endothelial cells under transient and persistent hypoxia: study using a 3D microvessels-on-chip model.
Mechanisms Controlling the Behavior of Vascular Smooth Muscle Cells in Hypoxic Pulmonary Hypertension.
Role of Paraoxonase 2 in Airway Epithelial Response to Oxidant Stress.
FBP1 over-expression suppresses HIF-1α in papillary thyroid cancer.
Modulators of Alpha-2 Macroglobulin Upregulation by High Glucose in Glomerular Mesangial Cells.
Mechanisms of METTL14-Mediated m6A Modification in Promoting Iron Overload-Induced Lipid Peroxidative Damage in Vascular Endothelial Cells to Aggravate Atherosclerosis.
Mechanistic exploration of ubiquitination-mediated pathways in cerebral ischemic injury.
Bioinformatic Analysis and Molecular Docking Identify Isorhamnetin Is a Candidate Compound in the Treatment of Pulmonary Artery Hypertension.
Stress fiber strain is zero in normal aortic smooth muscle, elevated in hypertensive stretch, and minimal in wall thickening rats.
Hypoxic Pulmonary Vasoconstriction: An Important Component of the Homeostatic Oxygen Sensing System.
Fosinopril inhibits Ang II-induced VSMC proliferation, phenotype transformation, migration, and oxidative stress through the TGF-β1/Smad signaling pathway.
BMP10 Knockdown Modulates Endothelial Cell Immunoreactivity by Inhibiting the HIF-1α Pathway in the Sepsis-Induced Myocardial Injury.
The role of fibromodulin in myocardial fibrosis in a diabetic cardiomyopathy rat model.
METTL3-Dependent YTHDF2 Mediates TSC1 Expression to Regulate Alveolar Epithelial Mesenchymal Transition and Promote Idiopathic Pulmonary Fibrosis.
RNA binding protein RBM22 suppresses non-small cell lung cancer tumorigenesis by stabilizing LATS1 mRNA.
The Role and Interactive Mechanism of Endoplasmic Reticulum Stress and Ferroptosis in Musculoskeletal Disorders.
Epigenetic mechanisms mediate cytochrome P450 1A1 expression and lung endothelial injury caused by MRSA in vitro and in vivo.
Long-Term Adverse Effects of Perinatal Hypoxia on the Adult Pulmonary Circulation Vary Between Males and Females in a Murine Model.
Endothelial Dysfunction with Aging: Does Sex Matter?
Metabolic Chaos in Kidney Disease: Unraveling Energy Dysregulation.
Influence of Hypoxia on the Airway Epithelium.
Complement System and Adhesion Molecule Skirmishes in Fabry Disease: Insights into Pathogenesis and Disease Mechanisms.
Hypoxia is linked to acquired resistance to immune checkpoint inhibitors in lung cancer.
Ca2+ Signaling in Cardiovascular Fibroblasts.
Wnt/β-catenin maintains epithelial IL-33 in the colonic stem and progenitor cell niche and drives its induction in colitis.
Endothelial eNOS deficiency causes podocyte injury through NFAT2 and heparanase in diabetic mice.
From oxidative stress to metabolic dysfunction: The role of TRPM2.

Tissue Barriers. 2024 Nov 25. 2431416

Metabolic alterations of endothelial cells under transient and persistent hypoxia: study using a 3D microvessels-on-chip model.

Kanchana Pandian, Anton Jan van Zonneveld, Amy Harms, Thomas Hankemeier.

  Numerous signaling pathways are activated during hypoxia to facilitate angiogenesis, promoting interactions among endothelial cells and initiating downstream signaling cascades. Although the pivotal role of the nitric oxide (NO) response pathway is well-established, the involvement of arginine-specific metabolism and bioactive lipid mechanisms in 3D flow-activated in vitro models remains less understood. In this study, we explored the levels of arginine-specific metabolites and bioactive lipids in human coronary artery endothelial cells (HCAECs) under both transient and persistent hypoxia. We compared targeted metabolite levels between a 2D static culture model and a 3D microvessels-on-chip model. Notably, we observed robust regulation of NO metabolites in both transient and persistent hypoxic conditions. In the 2D model under transient hypoxia, metabolic readouts of bioactive lipids revealed increased oxidative stress markers, a phenomenon not observed in the 3D microvessels. Furthermore, we made a novel discovery that the responses of bioactive lipids were regulated by hypoxia inducible factor-1α (HIF-1α) in the 2D cell culture model and partially by HIF-1α and flow-induced shear stress in the 3D microvessels. Immunostaining confirmed the HIF-1α-induced regulation under both hypoxic conditions. Real-time oxygen measurements in the 3D microvessels using an oxygen probe validated that oxygen levels were maintained in the 3D model. Overall, our findings underscore the critical regulatory roles of HIF-1α and shear stress in NO metabolites and bioactive lipids in both 2D and 3D cell culture models.

Keywords:  3D microvessels-on-chip model; endothelial dysfunction; hypoxia; hypoxia inducible factor – 1 alpha; nitric oxide metabolites; signaling lipids

DOI:  https://doi.org/10.1080/21688370.2024.2431416
Physiol Res. 2024 Nov 29. 73(S2): S569-S596

Mechanisms Controlling the Behavior of Vascular Smooth Muscle Cells in Hypoxic Pulmonary Hypertension.

L Bačáková, A Sedlář, J Musílková, A Eckhardt, M Žaloudíková, F Kolář, H Maxová.

Pulmonary hypertension is a complex and heterogeneous condition with five main subtypes (groups). This review focuses on pulmonary hypertension caused by chronic hypoxia (hypoxic pulmonary hypertension, HPH, group 3). It is based mainly on our own experimental work, especially our collaboration with the group of Professor Herget, whose fifth anniversary of death we commemorate. We have found that oxidation and degradation of the extracellular matrix (ECM) in vitro, in either the presence or the absence of pro-inflammatory cells, activate vascular smooth muscle cell (VSMC) proliferation. Significant changes in the ECM of pulmonary arteries also occurred in vivo in hypoxic rats, namely a decrease in collagen VI and an increase in matrix metalloproteinase 9 (MMP-9) in the tunica media, which may also contribute to the growth activation of VSMCs. The proliferation of VSMCs was also enhanced in their co-culture with macrophages, most likely due to the paracrine production of growth factors in these cells. However, hypoxia itself has a dual effect: on the one hand, it can activate VSMC proliferation and hyperplasia, but on the other hand, it can also induce VSMC hypertrophy and increased expression of contractile markers in these cells. The influence of hypoxia-inducible factors, microRNAs and galectin-3 in the initiation and development of HPH, and the role of cell types other than VSMCs (endothelial cells, adventitial fibroblasts) are also discussed. Keywords: Vasoconstriction, Remodeling, Oxidation, Degradation, Extracellular matrix, Collagen, Proteolytic enzymes, Metalloproteinases, Macrophages, Mast cells, Smooth muscle cells, Endothelial cells, Fibroblasts, Mesenchymal stem cells, Hypoxia-inducible factor, microRNA, Galectins, Hyperplasia, Hypertrophy, Therapy of hypoxic pulmonary hypertension.
Antioxidants (Basel). 2024 Oct 31. pii: 1333. [Epub ahead of print]13(11):

Role of Paraoxonase 2 in Airway Epithelial Response to Oxidant Stress.

Matthew S McCravy, Zhonghui Yang, Jaime Cyphert-Daly, Zachary R Healy, Aaron V Vose, Haein R Kim, Julia K L Walker, Robert M Tighe, Heath G Gasier, Jennifer L Ingram, Loretta G Que.

  Asthma is a widespread chronic lung disease characterized by airway inflammation and hyperresponsiveness. This airway inflammation is classified by either the presence (T2-high) or absence (T2-low) of high levels of eosinophils. Because most therapies for asthma target eosinophils and related pathways, treatment options for T2-low disease are limited. New pathophysiologic targets are needed. Oxidant stress is a common feature of T2-low disease. Airway epithelial expression of the antioxidant enzyme Paraoxonase 2 (PON2) is decreased in a well-recognized population of people with T2-low asthma and people with obesity and asthma. As a potential mechanism of increased oxidant stress, we measured the role of PON2 in lung oxidant responses using an environmentally relevant in vivo murine oxidant exposure (i.e., ozone) and in vitro studies with an immortalized human airway epithelial cell line BEAS-2B. Pon2-deficient (Pon2-/-) mice developed increased airway hyper-responsiveness compared to wild-type controls. Despite reduced alveolar macrophage influx, Pon2-/- mice exhibited increased nitrite production. In human airway epithelial cells incubated with hydrogen peroxide, PON2 knockdown (PON2KD) decreased mitochondrial function and inner mitochondrial membrane potential. These findings suggest that PON2 functions in defending against airway epithelial oxidant stress. Further studies are needed to elucidate the mechanisms linking PON2, oxidant stress, and asthma pathogenesis.

Keywords:  asthma; mitochondria; oxidant stress; ozone; paraoxonase

DOI:  https://doi.org/10.3390/antiox13111333
Sci Rep. 2024 11 25. 14(1): 29167

FBP1 over-expression suppresses HIF-1α in papillary thyroid cancer.

Huashui Li, Wenjun Xie, Xiangqin Huang, Yifan Chen.

  Papillary thyroid carcinoma (PTC) is generally a slow-growing disease with a favorable 10-year survival rate. However, about 10% of PTC cases show significant aggressiveness, with tendencies for local invasion or distant metastasis, the mechanisms of which remain unclear. This study aims to identify predictive indicators and explore new potential targets for clinical treatment, highlighting the need for novel biomarkers and therapeutic targets. We analyzed FBP1 expression in PTC tissues. Cell proliferation, apoptosis, and invasion were evaluated with and without FBP1 overexpression in PTC cells to assess FBP1's effects. We then investigated whether FBP1 reduces PTC cell tumorigenesis and metastasis by regulating HIF-1α expression. FBP1 expression was reduced in PTC samples and showed a negative correlation with T stage. In vitro experiments indicated that FBP1 acts as a hypoxia response inhibitor, regulating tumor cells. Additionally, FBP1 inhibited the proliferation, apoptosis, and invasion of thyroid cancer cells by modulating HIF-1α expression. Our results provide new insights into the role of FBP1 in PTC progression and indicate that targeting the FBP1-HIF-1α axis could be a promising therapeutic approach for this disease.

Keywords:  FBP1; HIF-1α; Hypoxia; Papillary thyroid tumor

DOI:  https://doi.org/10.1038/s41598-024-81017-6
Biomolecules. 2024 Nov 13. pii: 1444. [Epub ahead of print]14(11):

Modulators of Alpha-2 Macroglobulin Upregulation by High Glucose in Glomerular Mesangial Cells.

Jackie Trink, Renzhong Li, Bo Gao, Chao Lu, Joan C Krepinsky.

  Up to 40% of patients with diabetes mellitus will develop diabetic kidney disease (DKD), characterized pathologically by the accumulation of extracellular matrix proteins, which leads to the loss of kidney function over time. Our previous studies showed that the pan-protease inhibitor alpha 2-macroglobulin (A2M) is increased in DKD and is a critical regulator of the fibrotic response in glomerular mesangial cells (MC), an initial site of injury during DKD development. How A2M is regulated by high glucose (HG) has not yet been elucidated and is the focus of this investigation. Using serial deletions of the full A2M promoter, we identified the -405 bp region as HG-responsive in MC. Site-directed mutagenesis, siRNA, and ChIP studies showed that the transcription factor, nuclear factor of activated T cells 5 (NFAT5), regulated A2M promoter activity and protein expression in response to HG. Forkhead box P1 (FOXP1) served as a cooperative binding partner for NFAT5, required for A2M upregulation. Lastly, we showed that Smad3, known for its role in kidney fibrosis, regulated A2M promoter activity and protein production independently of HG. The importance of NFAT5, FOXP1, and Smad3 in A2M regulation was confirmed in ex vivo studies using isolated glomeruli. In conclusion, Smad3 is required for basal and HG-induced A2M expression, while NFAT5 and FOXP1 cooperatively regulate increased A2M transcription in response to HG. Inhibition of NFAT5/FOXP1 will be further evaluated as a potential therapeutic strategy to inhibit A2M production and attenuate profibrotic signaling in DKD.

Keywords:  FOXP1; NFAT5; Smad3; alpha 2-macroglobulin; diabetic kidney disease; promoter

DOI:  https://doi.org/10.3390/biom14111444
J Biochem Mol Toxicol. 2024 Dec;38(12): e70066

Mechanisms of METTL14-Mediated m6A Modification in Promoting Iron Overload-Induced Lipid Peroxidative Damage in Vascular Endothelial Cells to Aggravate Atherosclerosis.

Xiao-Li Min, Si-Xian Lin, Xiao-Hong Zhao, Qing Zhao, Yun-Fei Li, Xu-Hui Li, Xiao-Yong Liu, Yi Cao, Yu-Long Sun, Yong Zeng.

  Atherosclerosis (AS) is a chronic multifactorial disease with damage to vascular endothelial cells (VECs). This study sought to delve into the mechanism of methyltransferase-like 14 (METTL14) in iron overload-induced lipid peroxidative damage in AS. AS mouse model and cell model were established. Levels of METTL14/circRNA coded by the Arhgap12 (circARHGAP12)/Aspartate β-hydroxylase (ASPH) were determined. AS plaque area/lipid deposition/lipid metabolism in AS mice and iron overload in VECs were evaluated. N6-methyladenosine (m6A) level and METTL14 enrichment and human antigen R (HuR) in circARHGAP12 or ASPH were measured. The mRNA stability of circARHGAP12 or ASPH was analyzed. We observed that METTL14 was upregulated in AS mice. METTL14 downregulation reduced plaque area/lipid deposition/iron overload/peroxidative damage in AS mice. In cell models, METTL14 downregulation could VEC injury/iron overload/lipid peroxidative damage. Mechanically, METTL14 increased the stability and expression of circARHGAP12 through m6A modification, further stabilized ASPH mRNA, and promoted ASPH transcription by binding to HuR. Overexpression of circARHGAP12 or inhibition of ASPH averted the protective role of METTL14 downregulation against iron overload-induced peroxidative damage in AS. In conclusion, METTL14-mediated m6A modification upregulated circARHGAP12 and ASPH to aggravate overload-induced lipid peroxidative damage and facilitate AS progression.

Keywords:  METTL14; atherosclerosis; iron overload; peroxidative damage; vascular endothelial cell

DOI:  https://doi.org/10.1002/jbt.70066
Mol Biol Rep. 2024 Nov 28. 52(1): 22

Mechanistic exploration of ubiquitination-mediated pathways in cerebral ischemic injury.

Supriya Khanra, Shareen Singh, Thakur Gurjeet Singh.

  The ubiquitin-proteasome system (UPS) plays a pivotal role in regulating protein homeostasis and cellular processes, including protein degradation, trafficking, DNA repair, and cell signaling. During cerebral ischemia, ischemic conditions profoundly disrupt UPS activity, leading to proteasomal dysfunction and the accumulation of abnormal proteins. This imbalance contributes to neuronal injury and cell death observed in ischemic stroke. The UPS is intricately linked to various signaling pathways crucial for neuronal survival, inflammation, and cellular stress response, such as NF-κB, TRIM, TRIP, JAK-STAT, PI3K/Akt, and ERK1/2. Alterations in the ubiquitination process can significantly impact the activation and regulation of these pathways, exacerbating ischemic brain injury. Therapeutic approaches targeting the UPS in cerebral ischemia aim to rebalance protein levels, reduce proteotoxic stress, and mitigate neuronal injury. Strategies include proteasome inhibition, targeting specific ubiquitin ligases and deubiquitinating enzymes, and modulating ubiquitination-mediated regulation of key signaling pathways implicated in ischemia-induced pathophysiology. Therefore, the present review discusses the molecular mechanisms underlying UPS dysfunction in ischemic stroke is crucial for developing effective therapeutic interventions. Modulating ubiquitination-mediated pathways through therapeutic interventions targeting specific UPS components holds significant promise for mitigating ischemic brain injury and promoting neuroprotection and functional recovery in patients with cerebral ischemia.

Keywords:  Cerebral ischemia; ERK1/2); JAK-STAT; Neuroprotection; PI3K/Akt; Proteasomal dysfunction; Signaling pathway modulation (NF-κB; TRIM; TRIP; Ubiquitin-proteasome system (UPS)

DOI:  https://doi.org/10.1007/s11033-024-10123-5
Anatol J Cardiol. 2024 Nov 28.

Bioinformatic Analysis and Molecular Docking Identify Isorhamnetin Is a Candidate Compound in the Treatment of Pulmonary Artery Hypertension.

Chen Shao, Wei Xia, Yang Liu.

BACKGROUND: The current study aims to identify the key pathways and potential therapeutic targets for pulmonary arterial hypertension (PAH) and to further evaluate the anti-PAH effects of isorhamnetin.
METHODS: The dataset of gene expression profiling for PAH (GSE113439) was downloaded from the gene expression omnibus (GEO) database. Isorhamnetin target genes were extracted from the comparative toxicogenomics database (CTD). Various bioinformatics methods were employed to identify the core pathways associated with PAH and potential intervention targets. Molecular docking was conducted between the interacting target and the candidate compound, isorhamnetin.
RESULTS: One thousand nine hundred sixty-two upregulated genes and 642 downregulated genes were identified. Molecular complex detection analyses revealed that the significant biological processes associated with upregulated genes included DNA damage response, mitotic cell cycle, and chromosome organization. In contrast, the signifi ant biological processes related to downregulated genes encompassed cellular response to growth factor stimulus, response to growth factor, and blood vessel development. Immune infilt ation analysis indicated that PAH is associated with signifi ant changes in the distribution of immune cells and differential expression of immune checkpoints. Furthermore, 58 isorhamnetin targets were extracted from the CTD, and we identified 1 interacting gene, NFE2L2, among the differentially expressed genes (DEGs), DEGs related to ferroptosis, and isorhamnetin targets. Isorhamnetin demonstrated strong affinities with vascular endothelial growth factor (VEGF) receptors and transcription factors (ATM and ZNF24) associated with VEGFs, as well as the ferroptosis protein NFE2L2.
CONCLUSIONS: Pulmonary arterial hypertension is characterized by a series of abnormalities in downstream molecular signaling pathways, including DNA damage, immune dysregulation, VEGF signaling deficienc , and the ferroptosis process. These may represent the core pathophysiological mechanisms of PAH. Ferroptosis-related genes, such as NFE2L2 and TF (ATM, ZNF24) associated with VEGFs, are potential therapeutic targets that contribute to the mechanisms mentioned above. Isorhamnetin is a promising candidate compound for the treatment of PAH.

DOI: https://doi.org/10.14744/AnatolJCardiol.2024.4723
Sci Rep. 2024 Nov 29. 14(1): 29731

Stress fiber strain is zero in normal aortic smooth muscle, elevated in hypertensive stretch, and minimal in wall thickening rats.

Shukei Sugita, Rintaro Kawai, Yoshihiro Ujihara, Masanori Nakamura.

  Hypertension causes aortic wall thickening until the original wall stress is restored. We hypothesized that this regulation involves stress fiber (SF) tension transmission to the nucleus in smooth muscle cells (SMCs) and investigated the strain in the SF direction as a condition required for this transmission. Thoracic aortas from Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHRs) were examined. SFs in aortic SMCs were fluorescently labeled and observed under a confocal microscope while stretched along the circumferential (θ) axis. Three conditions were studied: WKY physiological (WKYphys; blood pressure changes from diastolic to systolic for WKY), high-strain state (WKYhigh; diastolic to hypertensive level for WKY simulating initial hypertension), and SHR physiological (SHRphys; diastolic to systolic for SHR simulating after wall-thickening). SF strain and direction were measured. The SF inclination angle from the θ axis was 18° ± 3° in WKYphys, 13° ± 2° in WKYhigh, and 20° ± 1° in SHRphys. SF strain was 0.01 ± 0.02 in WKYphys, 0.20 ± 0.04 in WKYhigh, and 0.02 ± 0.02 SHRphys. SF strain was minimal in WKYphys, significantly increased in WKYhigh, and reduced to approximately zero in SHRphys. These findings support SFs function as mechanosensors in response to hypertension.

Keywords:  Fluorescent microscopy; Hypertension; Normal strain; Stress fiber; Vascular smooth muscle cells

DOI:  https://doi.org/10.1038/s41598-024-81229-w
Physiol Res. 2024 Nov 29. 73(S2): S493-S510

Hypoxic Pulmonary Vasoconstriction: An Important Component of the Homeostatic Oxygen Sensing System.

S L Archer, K J Dunham-Snary, Ret Bentley, E Alizadeh, E K Weir.

Hypoxic pulmonary vasoconstriction (HPV) rapidly and reversibly matches lung ventilation (V) and perfusion (Q), optimizing oxygen uptake and systemic oxygen delivery. HPV occurs in small pulmonary arteries (PA), which uniquely constrict to hypoxia. Although HPV is modulated by the endothelium the core mechanism of HPV resides in PA smooth muscle cells (PASMC). The PASMC's mitochondrial oxygen sensor lies within the electron transport chain (ETC) and includes NDUFS2 in ETC Complex-I. PASMC mitochondria respond to hypoxia by varying production of reactive oxygen species (ROS) and hydrogen peroxide in proportion to alveolar oxygen tension. Hypoxic ROS inhibition results in a state of reduction which triggers a redox-mediated inhibition of oxygen-sensitive, voltage-gated, potassium channels, including Kv1.5 and Kv2.1. Kv channel inhibition depolarizes the PASMC, opening of large-conductance calcium channels (CaL), elevating cytosolic calcium and activating the contractile apparatus. HPV is strongest in small PAs where sensors (hypoxia-responsive mitochondria) and effectors (oxygen-sensitive K+ channels) are enriched. Oxygenation at birth reverses fetal HPV, contributing to the rapid neonatal drop in pulmonary vascular resistance (PVR). A similar mitochon-drial-K+ channel sensor-effector mechanism exists in the ductus arteriosus (DA), however in DASMC it is oxygen-induced increases in mitochondrial ROS that inhibit DASMC K+ channels, causing DA constriction. Atelectasis and pneumonia elicit HPV, which optimises V/Q matching, increasing systemic oxygenation. Whilst HPV in response to localized hypoxia in a single lung lobe does not increase PA pressure; global airway hypoxia, as occurs with altitude or sleep apnea, causes pulmonary hypertension. HPV can be inhibited by drugs, including calcium channel blockers, or used to maintain a dry operative field during single lung anesthesia for lung surgery. HPV does not normally cause lung edema but excessive, heterogenous HPV contributes to high altitude pulmonary edema. HPV is suppressed in COVID-19 pneumonia by a SARS-CoV-2 mitochondriopathy. HPV is a component of the body's homeostatic oxygen sensing system. Keywords: Ductus arteriosus, Redox, NDUFS2, Oxygen sensitive potassium, Channels, High altitude pulmonary edema (HAPE), Mitochondrial electron transport chain, COVID-19 pneumonia, Atelectasis.
Open Life Sci. 2024 ;19(1): 20220955

Fosinopril inhibits Ang II-induced VSMC proliferation, phenotype transformation, migration, and oxidative stress through the TGF-β1/Smad signaling pathway.

Siqi Chen, Lingxiang Ye.

  Fosinopril (FOS) is an angiotensin-converting enzyme inhibitor that can decrease angiotensin II (Ang II) formation, thereby reducing systemic vasoconstriction. This study investigated the impact of FOS on vascular smooth muscle cell (VSMC) phenotypic transformation in hypertension. Experiments using western blotting revealed that FOS inhibits the Ang II-induced downregulation of α-SMA and SM22α and the upregulation of OPN in VSMCs. In addition, CCK8 assays, EdU staining, and Transwell assays demonstrated that FOS reduces Ang II-induced increases in VSMC cell viability, proliferation, migration, and MMP2 and MMP9 expression. Moreover, immunofluorescence and ELISA experiments showed that FOS suppresses Ang II-induced increases in ROS levels, NAD(P)H activity, and NOX2 and NOX4 expression in VSMCs. Western blotting also indicated that FOS inhibits Ang II-induced increases in TGF-β1 and p-Smad2/3 expression in VSMCs. Finally, FOS mitigates Ang II-induced VSMC proliferation, phenotypic transformation, migration, and oxidative stress by inhibiting the TGF-β1/Smad signaling pathway. In conclusion, these results suggest that FOS could be effective in managing vascular diseases, including hypertension.

Keywords:  Ang II; VSMC; fosinopril; hypertension; oxidative stress; vascular remodeling

DOI:  https://doi.org/10.1515/biol-2022-0955
J Cell Mol Med. 2024 Nov;28(22): e70232

BMP10 Knockdown Modulates Endothelial Cell Immunoreactivity by Inhibiting the HIF-1α Pathway in the Sepsis-Induced Myocardial Injury.

Huan Guan, Jingyun Fang.

  Sepsis is a life-threatening syndrome triggered by a cascade of dysregulated immune responses. Sepsis-induced myocardial injury (SIMI) substantially impacts the survival time of septic patients. However, the molecular mechanisms underlying the pathology of SIMI remain unclear. Immune-related differentially expressed genes in SIMI were identified through RNA sequencing and bioinformatics analysis. The expression levels of hub genes were detected using reverse transcription quantitative PCR. BMP10 was knocked down in the lipopolysaccharide-induced mouse and cardiac microvascular endothelial cell (CMEC) models, and its functions were assessed by a series of in vitro and in vivo assays. Cell adhesion and HIF-1 pathway-associated protein expressions were measured by western blot. Fenbendazole-d3 was used to investigate whether BMP10 influenced SIMI development by modulating the HIF-1 pathway. Six key genes were screened, of which BMP10, HAMP, TRIM5, and MLANA were highly expressed, and PTPRN2 and AVP were lowly expressed. BMP10 knockdown ameliorated histopathological changes and inhibited apoptosis and CMEC immune infiltration in SIMI. BMP10 knockdown reduced inflammatory factor (IL-6, MCP-1, IFN-β, and CCL11) levels and protein expressions of cell adhesion-related molecules (VCAM-1 and ICAM-1). Mechanistically, the HIF-1 pathway agonist, Fenbendazole-d3, significantly reversed the inhibitory effects of BMP10 knockdown on SIMI in vitro, indicating that BMP10 knockdown impeded the development of SIMI by suppressing the HIF-1α pathway. BMP10 knockdown blocks SIMI progression by inhibiting the HIF-1α pathway, which provides a new potential therapeutic strategy for SIMI treatment.

Keywords:  BMP10; HIF‐1α pathway; sepsis‐induced myocardial injury

DOI:  https://doi.org/10.1111/jcmm.70232
FEBS Open Bio. 2024 Nov 26.

The role of fibromodulin in myocardial fibrosis in a diabetic cardiomyopathy rat model.

Xiyan Dai, Fan Yang, Dongping Chen, Lu Yang, Zhihui Dong, Can Chen, Jianmin Xiao.

  Diabetic cardiomyopathy (DCM) is pathologically characterized by excessive deposition of extracellular matrix proteins, leading to myocardial fibrosis. Fibromodulin (Fmod) plays a crucial role in the pathogenesis of fibrotic diseases. However, the role and mechanism of Fmod in DCM-related myocardial fibrosis remain unclear. In the present study, we established a DCM rat model and an in vitro model of rat primary cardiac fibroblasts (RPCFs) exposed to high glucose. We assessed mRNA and protein expression levels of Col1a1, Col3a1, α-SMA and Fmod in both models. Fmod-overexpressing (ov-Fmod) and Fmod-knockdown (si-Fmod) rat cardiac fibroblasts (RCFs) were generated. Subsequently, whole RNA sequencing was conducted on ov-Fmod RCFs. The gene Col15a1 was evaluated in the DCM rat and all cell models. The correlation between plasma levels of Fmod and Col15a1 in DCM rat models was assessed. Transcription and protein levels of Fmod, Col1a1, Col3a1 and α-SMA were significantly elevated in DCM rat hearts and RPCFs. In ov-Fmod RCFs, fibrosis markers were similarly increased, except for Col3a1, which decreased. The Col1a1/Col3a1 ratio was elevated. Conversely, knocking down Fmod yielded opposite results. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses indicated that Fmod participates in multiple fibrosis-related pathways, affecting Col15a1. Expression of Col15a1 was significantly decreased in all models, compared to controls, except in si-Fmod RCFs. Importantly, Col15a1 and Fmod in plasma exhibited an inverse relationship in DCM. In summary, Fmod is implicated in DCM, with Fmod overexpression downregulating Col15a1 and increasing the Col1a1/Col3a1 ratio. This mechanism may influence diastolic heart failure in DCM by modulating myocardial stiffness and elasticity.

Keywords:  diabetic cardiomyopathy; fibromodulin; myocardial fibrosis

DOI:  https://doi.org/10.1002/2211-5463.13935
J Cell Physiol. 2024 Nov 28.

METTL3-Dependent YTHDF2 Mediates TSC1 Expression to Regulate Alveolar Epithelial Mesenchymal Transition and Promote Idiopathic Pulmonary Fibrosis.

Min Liu, Yingying Sheng, Mengyu Li, Tianyu Pan, Wei Jiang, Yafei Zhang, Xin Pan, Cheng Huang, Jun Li, Yuanyuan Wang.

  Diffuse, progressive interstitial lung disease with few treatment options and low survival rates is known as idiopathic pulmonary fibrosis (IPF). Alveolar epithelial cell damage and dysfunction are the main features of IPF. TSC1 has been documented to exert a pivotal function in governing cellular growth, proliferation, and ontogenesis. This work investigated TSC1's function and mechanism in IPF. Mice were given BLM to cause pulmonary fibrosis, and A549 cells underwent epithelial mesenchymal transition (EMT) in response to TGF-β1. According to the data, TSC1 expression was reduced in IPF. Overexpression of TSC1 was established by adenopathy-associated virus in vivo and adenovirus in vitro to significantly block the EMT process. Besides, the findings from the RNA-sequencing analysis indicate that overexpression of TSC1 mitigated the EMT process by suppressing the activation of the AKT/mTOR pathway via downregulation of ACTN4 expression. To examine the upstream regulatory mechanism, we employed the SRAMP database to predict m6A modification of TSC1 mRNA, followed by verification of m6A modification levels and expression using MERIP-qPCR, Dot blot, RT-qPCR, and WB. The results indicated a high degree of m6A modification in TSC1 mRNA in pulmonary fibrosis. The expression of METTL3 was further found to be significantly elevated. METTL3 knockdown impeded EMT progression. METTL3 inhibits TSC1 expression by increasing TSC1 m6A modification through the reading protein YTHDF2. In conclusion, our study elucidated that the METTL3/YTHDF2/TSC1 signaling axis activates the AKT/mTOR pathway to promote the development of IPF. This study provides potential molecular-level therapeutic targets for IPF disease.

Keywords:  AKT/mTOR pathway; EMT; IPF; METTL3; TSC1; YTHDF2

DOI:  https://doi.org/10.1002/jcp.31473
J Mol Histol. 2024 Nov 29. 56(1): 15

RNA binding protein RBM22 suppresses non-small cell lung cancer tumorigenesis by stabilizing LATS1 mRNA.

Min Hou, Qingmei Huang, Shan Chen, Jing Lei, Yakun Zhang.

  Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality worldwide. Despite advancements in diagnostics and therapeutics, the prognosis for NSCLC remains poor, highlighting the urgent need for novel treatment options. RNA binding proteins, particularly RBM22, have emerged as significant contributors to cancer progression by influencing RNA splicing and gene expression. This study investigates the role of RBM22 in NSCLC and its potential as a therapeutic target. We focus on the effects of RBM22 on cell proliferation, invasion, stemness, and its interaction with LATS1 mRNA. RBM22 expression was assessed in samples and cell lines of NSCLC through techniques such as real-time PCR and western blot analysis. To modify RBM22 levels, overexpression and knockdown methods were employed utilizing vectors and siRNAs. We conducted assays for cell proliferation, invasion, and stemness to evaluate the effects of altering RBM22. The interaction between RBM22 and LATS1 mRNA was investigated using RNA immunoprecipitation. In addition, in vivo studies involving subdermal tumor and lung metastasis models in athymic mice were carried out to evaluate how changes in RBM22 influence the tumorigenic and metastatic characteristics of NSCLC. Our analysis revealed a significant underexpression of RBM22 in NSCLC tissues compared to adjacent healthy tissues. Increasing RBM22 expression in NSCLC cell lines led to a marked decrease in cellular proliferation, invasiveness, and stemness, while silencing RBM22 produced opposing effects. Further investigations confirmed that RBM22 directly interacts with LATS1 mRNA, thereby stabilizing and enhancing its expression. In vivo studies validated that elevated RBM22 expression substantially reduced tumor formation and pulmonary metastases, as evidenced by decreased tumor size, mass, and Ki-67 proliferation marker expression, along with a significant reduction in the number of metastatic nodules in the lungs. Our study demonstrates that RBM22 suppresses NSCLC by stabilizing LATS1 mRNA, which in turn reduces tumor growth and metastasis. Consequently, RBM22 emerges as a valuable therapeutic target for NSCLC, offering new strategies for addressing this challenging condition.

Keywords:  LATS1; Non-small cell lung cancer (NSCLC); RBM22; RNA binding proteins; Tumor suppression

DOI:  https://doi.org/10.1007/s10735-024-10285-3
Biomolecules. 2024 Oct 28. pii: 1369. [Epub ahead of print]14(11):

The Role and Interactive Mechanism of Endoplasmic Reticulum Stress and Ferroptosis in Musculoskeletal Disorders.

Zhou Guo, Ruimin Chi, Yawen Peng, Kai Sun, Haigang Liu, Fengjing Guo, Jiachao Guo.

  Endoplasmic reticulum (ER) stress is a cellular phenomenon that arises in response to the accumulation of misfolded proteins within the ER. This process triggers the activation of a signalling pathway known as the unfolded protein response (UPR), which aims to restore ER homeostasis by reducing protein synthesis, increasing protein degradation, and promoting proper protein folding. However, excessive ER stress can perturb regular cellular function and contribute to the development of diverse pathological conditions. As is well known, ferroptosis is a kind of programmed cell death characterized by the accumulation of lipid peroxides and iron-dependent reactive oxygen species (ROS), resulting in oxidative harm to cellular structures. In recent years, there has been increasing evidence indicating that ferroptosis occurs in musculoskeletal disorders (MSDs), with emerging recognition of the complex relationship between ER stress and ferroptosis. This review presents a summary of ER stress and the ferroptosis pathway. Most importantly, it delves into the significance of ER stress in the ferroptosis process within diverse skeletal or muscle cell types. Furthermore, we highlight the potential benefits of targeting the correlation between ER stress and ferroptosis in treating degenerative MSDs.

Keywords:  MSDs; endoplasmic reticulum stress; ferroptosis; iron homeostasis; lipid metabolism

DOI:  https://doi.org/10.3390/biom14111369
FASEB J. 2024 Nov 30. 38(22): e70205

Epigenetic mechanisms mediate cytochrome P450 1A1 expression and lung endothelial injury caused by MRSA in vitro and in vivo.

Alison W Ha, Lucille N Meliton, Weiguo Chen, Lichun Wang, Mark Maienschein-Cline, Jeffrey R Jacobson, Eleftheria Letsiou, Steven M Dudek.

Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of severe pneumonia and acute respiratory distress syndrome (ARDS). To advance our mechanistic understanding of this important pathogen, we characterized the effects of MRSA-induced epigenetic modification of histone 3 lysine 9 acetylation (H3K9ac), an activator of gene transcription, on lung endothelial cells (EC), a critical site of ARDS pathophysiology. Chromatin immunoprecipitation and sequencing (ChIP-seq) analysis revealed that MRSA induces H3K9ac in the promoter regions of multiple genes, with the highest ranked peak annotated to the CYP1A1 gene. Subsequent experiments confirm that MRSA increases CYP1A1 protein and mRNA expression, and its enzymatic activity in EC. Epigenetic inhibitors (C646, RVX-208) reduce MRSA-induced CYP1A1 expression and inflammatory responses, including cytokine release and adhesion molecule expression. Inhibition of the Aryl hydrocarbon receptor (Ahr), a known mediator of CYP1A1 expression, blocks MRSA-induced upregulation of CYP1A1 mRNA and protein expression, enzyme activity, and cytokine release. Reduction of CYP1A1 protein expression by siRNA or inhibition of its activity by rhapontigenin attenuated MRSA-induced EC permeability and inflammatory responses. In a mouse model of MRSA-induced acute lung injury (ALI), inhibition of CYP1A1 activity by rhapontigenin improved multiple indices of ALI, including bronchoalveolar lavage (BAL) protein concentration, cytokine levels, and markers of endothelial damage. Analysis of publicly available data suggests upregulation of CYP1A1 expression in ARDS patients compared to ICU controls. In summary, these studies provide new insights into MRSA-induced lung injury and identify a novel functional role for epigenetic upregulation of CYP1A1 in lung EC during ARDS pathogenesis.

DOI: https://doi.org/10.1096/fj.202401812R
Physiol Res. 2024 Nov 29. 73(S2): S541-S556

Long-Term Adverse Effects of Perinatal Hypoxia on the Adult Pulmonary Circulation Vary Between Males and Females in a Murine Model.

A-C Peyter, V Muehlethaler, J-F Tolsa.

Adverse events during the perinatal period are associated with an increased risk to develop cardiometabolic diseases later in life. We established a murine model to study long-term effects of perinatal hypoxia (PH) on the pulmonary circulation. We previously demonstrated that PH led to an impaired regulation of pulmonary vascular tone in adulthood, linked to alterations in K+ channels in males and in the nitric oxide (NO)/cyclic guanosine monophosphate pathway in females. Moreover, simultaneous administration of inhaled NO (iNO) during PH exposure prevented adverse effects of PH on adult pulmonary vasculature in females. The present study showed that PH induced a significant increase in right ventricular pressure in males and females, and an enhanced sensitivity to acute hypoxia in females. PH significantly reduced acetylcholine-induced relaxation in pulmonary artery, to a greater extent in females than in males. PH led to right ventricular hypertrophy in adulthood, appearing earlier in males than in females. Morphometric measurements showed a significant increase in the number of 25-75-µm pulmonary vessels in male lungs following PH, probably resulting in increased pulmonary vascular resistance. The effects of prolonged hypoxia in adulthood differed between males and females. Perinatal iNO during PH prevented PH-induced alterations in the cardiopulmonary system, whereas perinatal iNO alone could have some adverse effects. Therefore, PH led to long-lasting alterations in the regulation of adult pulmonary circulation, which vary between males and females. In males, the increased pulmonary vascular resistance was associated with morphological changes besides functional alterations, whereas females showed an important pulmonary vascular dysfunction. Keywords: Perinatal hypoxia, Pulmonary circulation, Endothelium-dependent relaxation, Phosphodiesterases, Sex differences.
Int J Mol Sci. 2024 Nov 13. pii: 12203. [Epub ahead of print]25(22):

Endothelial Dysfunction with Aging: Does Sex Matter?

Jakub Jozue Wojtacha, Barbara Morawin, Edyta Wawrzyniak-Gramacka, Anna Tylutka, Ana Karyn Ehrenfried de Freitas, Agnieszka Zembron-Lacny.

  Oxidative stress and inflammation accompany endothelial dysfunction that results from the excessive or uncontrolled production of reactive oxygen and nitrogen species (RONS) in older adults. This study was designed to assess the usefulness of serum oxi-inflammatory component combinations in vascular disease prediction and prevention with regard to sex. Women (n = 145) and men (n = 50) aged 72.2 ± 7.8 years participated in this project. The females demonstrated the elevated production of hydrogen peroxide (H2O2) and nitric oxide (NO) responsible for intravascular low-density lipoprotein oxidation. NO generation was enhanced in the women, but its bioavailability was reduced, which was expressed by a high 3-nitrotyrosine (3-NitroT) concentration. The relation of NO/3-NitroT (rs = 0.811, p < 0.001) in the women and NO/3-NitroT (rs = -0.611, p < 0.001) in the men showed that sex determines endothelial dysfunction. RONS generation in the women simultaneously promoted endothelial regeneration, as demonstrated by a ~1.5-fold increase in circulating progenitor cells. Inflammation-specific variables, such as the neutrophil-to-lymphocyte ratio, the systemic immune inflammation index, and the neutrophil-to-high-density lipoprotein (HDL) ratio, were reduced in the women and showed their diagnostic utility for clinical prognosis in vascular dysfunction, especially the C-reactive-protein-to-HDL ratio (AUC = 0.980, specificity 94.7%, sensitivity 93.3%, OR = 252, 95% CI 65-967, p < 0.001). This study is the first to have revealed sex-specific changes in the oxi-inflammatory response, which can generate the risk of cardiovascular events at an older age.

Keywords:  3-nitrotyrosine; blood cell count; endothelial progenitor cells; nitric oxide; older adults; systemic inflammatory index

DOI:  https://doi.org/10.3390/ijms252212203
J Clin Med. 2024 Nov 11. pii: 6772. [Epub ahead of print]13(22):

Metabolic Chaos in Kidney Disease: Unraveling Energy Dysregulation.

Priya Gupta, Saiya Zhu, Yuan Gui, Dong Zhou.

   BACKGROUND: Acute kidney injury (AKI) and chronic kidney disease (CKD) share a fundamental disruption: metabolic dysfunction.
METHODS: A literature review was performed to determine the metabolic changes that occur in AKI and CKD as well as potential therapeutic targets related to these changes.
RESULTS: In AKI, increased energy demand in proximal tubular epithelial cells drives a shift from fatty acid oxidation (FAO) to glycolysis. Although this shift offers short-term support, it also heightens cellular vulnerability to further injury. As AKI progresses to CKD, metabolic disruption intensifies, with both FAO and glycolysis becoming downregulated, exacerbating cellular damage and fibrosis. These metabolic alterations are governed by shifts in gene expression and protein signaling pathways, which can now be precisely analyzed through advanced omics and histological methods.
CONCLUSIONS: This review examines these metabolic disturbances and their roles in disease progression, highlighting therapeutic interventions that may restore metabolic balance and enhance kidney function. Many metabolic changes that occur in AKI and CKD can be utilized as therapeutic targets, indicating a need for future studies related to the clinical utility of these therapeutics.

Keywords:  AKI; CKD; FAO; energy metabolism; glycolysis

DOI:  https://doi.org/10.3390/jcm13226772
Physiol Res. 2024 Nov 29. 73(S2): S557

Influence of Hypoxia on the Airway Epithelium.

K Procházková, J Uhlík.

The necessity of oxygen for metabolic processes means that hypoxia can lead to serious cell and tissue damage. On the other hand, in some situations, hypoxia occurs under physiological conditions and serves as an important regulation factor. The airway epithelium is specific in that it gains oxygen not only from the blood supply but also directly from the luminal air. Many respiratory diseases are associated with airway obstruction or excessive mucus production thus leading to luminal hypoxia. The main goal of this review is to point out how the airway epithelium reacts to hypoxic conditions. Cells detect low oxygen levels using molecular mechanisms involving hypoxia-inducible factors (HIFs). In addition, the cells of the airway epithelium appear to overexpress HIFs in hypoxic conditions. HIFs then regulate many aspects of epithelial cell functions. The effects of hypoxia include secretory cell stimulation and hyperplasia, epithelial barrier changes, and ciliogenesis impairment. All the changes can impair mucociliary clearance, exacerbate infection, and promote inflammation leading to damage of airway epithelium and subsequent airway wall remodeling. The modulation of hypoxia regulatory mechanisms may be one of the strategies for the treatment of obstructive respiratory diseases or diseases with mucus hyperproduction. Keywords: Secretory cells, Motile cilia, Epithelial barrier, Oxygenation, Obstructive respiratory diseases.
Int J Mol Sci. 2024 Nov 14. pii: 12252. [Epub ahead of print]25(22):

Complement System and Adhesion Molecule Skirmishes in Fabry Disease: Insights into Pathogenesis and Disease Mechanisms.

Albert Frank Magnusen, Manoj Kumar Pandey.

  Fabry disease is a rare X-linked lysosomal storage disorder caused by mutations in the galactosidase alpha (GLA) gene, resulting in the accumulation of globotriaosylceramide (Gb3) and its deacetylated form, globotriaosylsphingosine (Lyso-Gb3) in various tissues and fluids throughout the body. This pathological accumulation triggers a cascade of processes involving immune dysregulation and complement system activation. Elevated levels of complement 3a (C3a), C5a, and their precursor C3 are observed in the plasma, serum, and tissues of patients with Fabry disease, correlating with significant endothelial cell abnormalities and vascular dysfunction. This review elucidates how the complement system, particularly through the activation of C3a and C5a, exacerbates disease pathology. The activation of these pathways leads to the upregulation of adhesion molecules, including vascular cell adhesion molecule 1 (VCAM1), intercellular adhesion molecule 1 (ICAM1), platelet and endothelial cell adhesion molecule 1 (PECAM1), and complement receptor 3 (CR3) on leukocytes and endothelial cells. This upregulation promotes the excessive recruitment of leukocytes, which in turn exacerbates disease pathology. Targeting complement components C3a, C5a, or their respective receptors, C3aR (C3a receptor) and C5aR1 (C5a receptor 1), could potentially reduce inflammation, mitigate tissue damage, and improve clinical outcomes for individuals with Fabry disease.

Keywords:  cell adhesion molecules; complement-mediated injury; endothelial dysfunction; immune cell infiltration; inflammatory cascade

DOI:  https://doi.org/10.3390/ijms252212252
J Exp Med. 2025 Jan 06. pii: e20231106. [Epub ahead of print]222(1):

Hypoxia is linked to acquired resistance to immune checkpoint inhibitors in lung cancer.

Camila Robles-Oteíza, Katherine Hastings, Jungmin Choi, Isabelle Sirois, Arvind Ravi, Francisco Expósito, Fernando de Miguel, James R Knight, Francesc López-Giráldez, Hyejin Choi, Nicholas D Socci, Taha Merghoub, Mark Awad, Gad Getz, Justin Gainor, Matthew D Hellmann, Étienne Caron, Susan M Kaech, Katerina Politi.

Despite the established use of immune checkpoint inhibitors (ICIs) to treat non-small cell lung cancer (NSCLC), only a subset of patients benefit from treatment and ∼50% of patients whose tumors respond eventually develop acquired resistance (AR). To identify novel drivers of AR, we generated murine Msh2 knock-out (KO) lung tumors that initially responded but eventually developed AR to anti-PD-1, alone or in combination with anti-CTLA-4. Resistant tumors harbored decreased infiltrating T cells and reduced cancer cell-intrinsic MHC-I and MHC-II levels, yet remained responsive to IFNγ. Resistant tumors contained extensive regions of hypoxia, and a hypoxia signature derived from single-cell transcriptional profiling of resistant cancer cells was associated with decreased progression-free survival in a cohort of NSCLC patients treated with anti-PD-1/PD-L1 therapy. Targeting hypoxic tumor regions using a hypoxia-activated pro-drug delayed AR to ICIs in murine Msh2 KO tumors. Thus, this work provides a rationale for targeting tumor metabolic features, such as hypoxia, in combination with immune checkpoint inhibition.

DOI: https://doi.org/10.1084/jem.20231106
Biomolecules. 2024 Oct 27. pii: 1365. [Epub ahead of print]14(11):

Ca2+ Signaling in Cardiovascular Fibroblasts.

Andreas Rinne, Florentina Pluteanu.

  Fibrogenesis is a physiological process required for wound healing and tissue repair. It is induced by activation of quiescent fibroblasts, which first proliferate and then change their phenotype into migratory, contractile myofibroblasts. Myofibroblasts secrete extracellular matrix proteins, such as collagen, to form a scar. Once the healing process is terminated, most myofibroblasts undergo apoptosis. However, in some tissues, such as the heart, myofibroblasts remain active and sensitive to neurohumoral factors and inflammatory mediators, which lead eventually to excessive organ fibrosis. Many cellular processes involved in fibroblast activation, including cell proliferation, protein secretion and cell contraction, are highly regulated by intracellular Ca2+ signals. This review summarizes current research on Ca2+ signaling pathways underlying fibroblast activation. We present receptor- and ion channel-mediated Ca2+ signaling pathways, discuss how localized Ca2+ signals of the cell nucleus may be involved in fibroblast activation and present Ca2+-sensitive transcription pathways relevant for fibroblast biology. When investigated, we highlight how the function of Ca2+-handling proteins changes during cardiac and pulmonary fibrosis. Many aspects of Ca2+ signaling remain unexplored in different types of cardiovascular fibroblasts in relation to pathologies, and a better understanding of Ca2+ signaling in fibroblasts will help to design targeted therapies against fibrosis.

Keywords:  Ca2+ ion channels; Ca2+ signaling; Ca2+ transport mechanisms; cardiac fibrosis; fibroblast; myofibroblast; pulmonary fibrosis

DOI:  https://doi.org/10.3390/biom14111365
Mucosal Immunol. 2024 Nov 24. pii: S1933-0219(24)00115-6. [Epub ahead of print]

Wnt/β-catenin maintains epithelial IL-33 in the colonic stem and progenitor cell niche and drives its induction in colitis.

Michael A Schumacher, Megan H Thai, Jonathan J Hsieh, Alexa Gramajo, Cambrian Y Liu, Mark R Frey.

  Interleukin (IL)-33 is a key responder to intestinal injury and inflammation. In the colon, it is expressed by several cell populations, with the specific cellular source likely determining its role. The colonic epithelium expresses IL-33; however, the factors controlling its production and the specific epithelial lineage(s) expressing IL-33 are poorly understood. We recently reported that colonic epithelial IL-33 is induced by inhibition of glycogen synthase kinase-3β (GSK3β), but the signaling pathway mediating this induction is unknown. Here we tested the role of Wnt/β-catenin signaling in regulating colonic epithelial IL-33 at homeostasis and in injury-induced colitis. Transcriptomic analysis shows that epithelial IL-33 localizes to stem and progenitor cells. Ligand activation of Wnt/β-catenin signaling induced IL-33 in colonic organoid and cell cultures. Furthermore, small-molecule disruption of β-catenin interaction with cyclic AMP response element binding protein (CBP) prevented epithelial IL-33 induction. Antagonism of CBP/β-catenin signaling also prevented rapid epithelial IL-33 induction in dextran sodium sulfate (DSS)-mediated colitis, and was associated with maintenance of crypt-expressed host defense peptides. Together, these findings show β-catenin-driven production of epithelial IL-33 is an early response to colonic injury that shapes the crypt base defense response and suggest an immunoregulatory role for the stem cell niche in tissue injury.

Keywords:  CBP/β-catenin; Colon; Epithelium; IL-33; Wnt

DOI:  https://doi.org/10.1016/j.mucimm.2024.11.007
Sci Rep. 2024 11 25. 14(1): 29179

Endothelial eNOS deficiency causes podocyte injury through NFAT2 and heparanase in diabetic mice.

Daisuke Katagiri, Shinya Nagasaka, Keiko Takahashi, Suwan Wang, Ambra Pozzi, Roy Zent, Akira Shimizu, Ming-Zhi Zhang, Joachim R Göthert, Toin H van Kuppevelt, Raymond C Harris, Takamune Takahashi.

  The pivotal role of endothelial nitric oxide synthase (eNOS) in diabetic nephropathy (DN) has been demonstrated using global eNOS knockout (eNOSGKO) mice. However, the precise role of endothelially expressed eNOS and how its deficiency advances DN are still unclear. Here, we targeted endothelial eNOS expression (E-eNOSKO) after the onset of diabetes using the floxed eNOS and endSCL-CreERT alleles. Diabetes was induced by low-dose streptozotocin injections. To evaluate the role of nuclear factor of activated T cells-2 (NFAT2) in podocyte injury in this condition, podocyte-specific NFAT2KO mice were also generated on eNOSGKO mice. The mechanisms of podocyte injury were investigated using cultured podocytes. Compared with diabetic wild-type mice, diabetic E-eNOSKO mice showed more advanced DN accompanied by NFAT2 expression in podocytes. NO donor suppressed NFAT2 expression and activation in high-glucose cultured podocytes as well as in diabetic E-eNOSKO mice. Furthermore, podocyte-specific deletion of NFAT2 attenuated DN in diabetic eNOSGKO mice accompanied by decreased heparanase (HPSE) expression in podocytes. Consistent with this finding, HPSE was upregulated by NFAT2 transfection and suppressed by NFAT2 siRNA or NO donor treatment in cultured podocytes. HPSE transfection reduced podocyte attachment to extracellular matrix concurrent with syndecan-4 (SDC4) shedding, and this effect was attenuated by co-transfection of SDC4. Finally, HPSE inhibitor treatment attenuated podocyte injury in diabetic E-eNOSKO mice with increased SDC4 expression in podocytes. Collectively, our data suggest that endothelial eNOS deficiency causes podocyte HPSE expression in diabetic mice through NFAT2, and HPSE promotes podocyte detachment in part through SDC4 shedding, advancing DN.

Keywords:  Diabetic nephropathy; Heparanase; NFAT2; Podocyte; eNOS

DOI:  https://doi.org/10.1038/s41598-024-79501-0
Int J Biol Macromol. 2024 Nov 25. pii: S0141-8130(24)08892-5. [Epub ahead of print] 138081

From oxidative stress to metabolic dysfunction: The role of TRPM2.

Ying-Shuang Li, Hua-Cheng Ren, Hui Li, Man Xing, Jian-Hua Cao.

  Metabolic syndromes including atherosclerosis, diabetes, obesity, and hypertension are increasingly prevalent worldwide. The disorders are the primary attributes of oxidative stress and inflammation. The transient receptor potential M2 (TRPM2) channel is a pivotal mediator linking oxidative stress to metabolic dysfunction. TRPM2, a non-selective cation channel activated by reactive oxygen species (ROS) and adenosine diphosphate ribose (ADPR), regulates calcium influx, inflammation, and cell death across various tissues. This review explores the structural and activation mechanisms of TRPM2, emphasizing its significance in metabolic diseases. Elevated levels of TRPM2 play a vital role in the disease progression by influencing physiological and cellular processes such as endothelial dysfunction, immune cell activation, and mitochondrial impairment. In conditions such as atherosclerosis, ischemic stroke, diabetes, obesity, and hypertension; TRPM2 exacerbates oxidative damage, amplifies inflammatory responses, and disrupts metabolic homeostasis. Recent research highlights the potential of TRPM2 as a therapeutic target, developing specified inhibitors. This review underscores the multifaceted role of TRPM2 in metabolic disorders and its promise as a target for therapeutic interventions.

Keywords:  Metabolic dysfunction; Oxidative stress; The transient receptor potential M2

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.138081