bims-kishpe 2025-01-05 papers

bims-kishpe

Biomed News

on HSP70 role in hypoxia and metabolism in ECs

Issue of 2025–01–05
nine papers selected by
Alia Ablieh, Universität Heidelberg

GATA2 participates in protection against hypoxia-induced pulmonary vascular remodeling.
HIF-1α mediates hypertension and vascular remodeling in sleep apnea via hippo-YAP pathway activation.
Tumor hypoxia evidences the differential regulation of Mdm2-p53 axis by PTEN in tumor derived vs. normal endothelial cells.
Endothelial Cell-Selective Adhesion Molecule Deficiency Exhibit Increased Pulmonary Vascular Resistance Due to Impaired Endothelial Nitric Oxide Signaling.
Exploiting Mitochondria by Triggering a Faulty Unfolded Protein Response Leads to Effective Cardioprotection.
Understanding the impact of ER stress on lung physiology.
MANF overexpression ameliorates oxidative stress-induced apoptosis of human nucleus pulposus cells by facilitating mitophagy through promoting MFN2 expression.
Big data analytics and scRNA-seq in human aortic aneurysms and dissections: role of endothelial MerTK.
Localized molecular chaperone synthesis maintains neuronal dendrite proteostasis.

PLoS One. 2024 ;19(12): e0315446

GATA2 participates in protection against hypoxia-induced pulmonary vascular remodeling.

Yuko Shirota, Shin'ya Ohmori, James Douglas Engel, Takashi Moriguchi.

The vascular endothelium is vital for cardio-pulmonary homeostasis and, thus, plays a crucial role in preventing life-threatening lung diseases. The transcription factor GATA2 is essential for hematopoiesis and maintaining vascular integrity. Heterozygous mutations in GATA2 can lead to a primary immunodeficiency syndrome with pulmonary manifestations. Some GATA2 haploinsufficient patients develop pulmonary hypertension (PH), characterized by vascular remodeling and occlusion of small pulmonary arteries. However, the mechanism underlying pulmonary vascular remodeling in GATA2 haploinsufficient patients remain unclear. To understand how GATA2 deficiency affects pulmonary artery homeostasis, we applied a chronic hypoxia-mediated PH model using inducible systemic Gata2 conditionally deficient (G2-CKO) mice. The G2-CKO mice exhibited augmented pulmonary vascular remodeling, with enhanced α-smooth muscle actin accumulation and increased apoptotic cells in the vascular wall upon chronic hypoxia. Transcript analysis and chromatin immunoprecipitation assays using mouse pulmonary vascular endothelial cells revealed that GATA2 directly regulates the expression of G6pdx (a crucial cytoprotective enzyme) and Bmp4 (a growth factor that mediates vascular homeostasis). These results suggest that GATA2-deficient lungs are vulnerable to the hypoxic stress due to a diminished cellular protective response, making G2-CKO mice more prone to vascular remodeling upon chronic hypoxia. These findings provide insights into the mechanisms underlying GATA2-haploinsufficiency-related pulmonary hypertension.

DOI: https://doi.org/10.1371/journal.pone.0315446
Mol Med. 2024 Dec 28. 30(1): 281

HIF-1α mediates hypertension and vascular remodeling in sleep apnea via hippo-YAP pathway activation.

Shoude Zhang, Yuan Zhao, Zhanwei Dong, Mao Jin, Ying Lu, Mina Xu, Hong Pan, Guojin Zhou, Mang Xiao.

   BACKGROUND: Sleep apnea syndrome (SAS) is associated with hypertension and vascular remodeling. Hypoxia-inducible factor-1α (HIF-1α) and the Hippo-YAP pathway are implicated in these processes, but their specific roles remain unclear. This study investigated the HIF-1α/Hippo-YAP pathway in SAS-related hypertension.
METHODS: We established a rat model of SAS-induced hypertension via chronic intermittent hypoxia (CIH). Rats were treated with siRNA targeting HIF-1α. Blood pressure, inflammation, oxidative stress, vascular remodeling, and VSMC function were assessed. In vitro experiments with A7r5 cells and human aortic smooth muscle cells (HAoSMCs) explored the effects of HIF-1α silencing and YAP1 overexpression.
RESULTS: Compared with the control group, the CIH group presented significant increases in both HIF-1α and YAP1 expression, which correlated with increased blood pressure and vascular changes. HIF-1α silencing reduced hypertension, oxidative stress, inflammation, and the severity of vascular remodeling. Specifically, siRNA treatment for HIF-1α normalized blood pressure, decreased the levels of oxidative damage markers (increased SOD and decreased MDA), and reversed the changes in the levels of inflammatory markers (decreased high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6) and soluble E-selectin (sE-s)). Structural analyses revealed reduced vascular smooth muscle cell proliferation and collagen deposition, along with normalization of cellular markers, such as α-SMA and TGF-β1. Furthermore, the Hippo-YAP pathway appeared to mediate these effects, as evidenced by altered YAP1 expression and activity upon HIF-1α modulation.
CONCLUSIONS: Our findings demonstrate the significance of the HIF-1α/Hippo-YAP pathway in CIH-induced hypertension and vascular remodeling. HIF-1α contributes to these pathophysiological processes by promoting oxidative stress, inflammation, and aberrant VSMC behavior. Targeting this pathway could offer new therapeutic strategies for CIH-related cardiovascular complications in SAS patients.

Keywords:  HIF-1α, Hippo; Inflammation; Sleep apnea syndrome; Vascular remodeling; YAP

DOI:  https://doi.org/10.1186/s10020-024-00987-5
Sci Rep. 2024 Dec 30. 14(1): 31747

Tumor hypoxia evidences the differential regulation of Mdm2-p53 axis by PTEN in tumor derived vs. normal endothelial cells.

Kinga Wilkus-Adamczyk, Klaudia Brodaczewska, Claudine Kieda.

  Hypoxia, a condition of oxygen tension lower than physiological level, plays a crucial role in shaping the tumor microenvironment and modulates distinct cell populations activity. The tumor suppressor PTEN regulates angiogenesis, a process involving endothelial cells (ECs). Pathological in tumors, it is crucial for growth. As PTEN modulates p53, a key regulator of the ECs growth/angiogenic activity, it appears to be a target enabling the repair of the pathologic angiogenesis. This study aims to compare ECs derived from breast cancer (HBCa.MEC) site with those derived from the healthy breast tissue (HBH.MEC). Hypoxia increased angiogenic activity in HBCa.MEC vs. HBH.MEC, as showed an increased. Ability to form vessels in vitro. Low pO2 reduced the total level of Mdm2 and PTEN protein expression leading to elevated levels of their phosphorylation-dependent activity in HBCa.MEC, what was not changed in healthy ECs. Additionally, when Mdm2-p53 interaction was inhibited, hypoxic HBCa.MEC angiogenic activity was reduced reaching the normoxic ECs response. In conclusion, the PTEN-mediated control of pathological angiogenesis occurs by modulation of Mdm2/p53 interaction in the context of breast tumor microenvironment. PTEN emerges as a potential therapeutic target for normalizing tumor vessels in breast cancer treatment strategies.

Keywords:  ECs; Mdm2-p53; Nutlin-3; PTEN; Pathological angiogenesis

DOI:  https://doi.org/10.1038/s41598-024-82638-7
Am J Physiol Heart Circ Physiol. 2024 Dec 31.

Endothelial Cell-Selective Adhesion Molecule Deficiency Exhibit Increased Pulmonary Vascular Resistance Due to Impaired Endothelial Nitric Oxide Signaling.

Vadym Buncha, Liwei Lang, Katie Anne Fopiano, Daria V Ilatovskaya, Gaston Kapuku, Alexander Verin, Zsolt Bagi.

  Endothelial cell-selective adhesion molecule (ESAM) is a member of tight junction molecules, highly abundant in the heart and the lung, and plays a role in regulating endothelial cell permeability. We previously reported that mice with genetic ESAM deficiency (ESAM-/-) exhibit coronary microvascular dysfunction leading to the development of left ventricular diastolic dysfunction. Here, we hypothesize that ESAM-/- mice display impairments in the pulmonary vasculature, affecting the overall pulmonary vascular resistance (PVR). We utilized ESAM-/- mice and employed isolated, ventilated and perfused whole lung preparation to assess PVR independently of cardiac function. PVR was assessed in response to stepwise increases in flow, and also in response to perfusion of the endothelium-dependent agonist, bradykinin, the thromboxane analog, U46619, and the nitric oxide (NO) donor sodium nitroprusside (SNP). We found that PVR, at every applied flow rate, is significantly elevated in ESAM-/- mice compared to WT mice. Bradykinin-induced reduction in PVR and U46619-induced increase in PVR were both diminished in ESAM-/- mice, whereas SNP-induced responses were similar in WT and ESAM-/- mice. Inhibition of NO synthase with N(ω)-nitro-L-arginine methyl ester increased agonist-induced PVR in WT, but not in ESAM-/- mice. Pulmonary arteries isolated from ESAM-/- mice exhibited a reduced level of phospho-Ser473-Akt and phospho-Ser1177-eNOS. Furthermore, in human lung microvascular endothelial cells cultured under flow conditions, we found that siRNA-mediated knockdown of ESAM impaired fluid shear stress-induced endothelial cell alignment. Thus, we suggest that ESAM plays an important role in the endothelium-dependent, flow/shear stress- and vasoactive agonist-stimulated, NO-mediated maintenance of PVR in mice.

Keywords:  ESAM; nitric oxide synthase; pulmonary artery; pulmonary vascular resistance

DOI:  https://doi.org/10.1152/ajpheart.00593.2024
Int J Med Sci. 2025 ;22(1): 188-196

Exploiting Mitochondria by Triggering a Faulty Unfolded Protein Response Leads to Effective Cardioprotection.

Yang Shen, Xin Gao, Ying Xiang, Hao Zhou, Hang Zhu, Qiang Wu, Jinfeng Liu.

  This study investigates the role of Fundc1 in cardiac protection under high-altitude hypoxic conditions and elucidates its underlying molecular mechanisms. Using cardiomyocyte-specific Fundc1 knockout (Fundc1CKO ) mice, we demonstrated that Fundc1 deficiency exacerbates cardiac dysfunction under simulated high-altitude hypoxia, manifesting as impaired systolic and diastolic function. Mechanistically, we identified that Fundc1 regulates cardiac function through the mitochondrial unfolded protein response (mito-UPR) pathway. Fundc1 deficiency led to significant downregulation of multiple mito-UPR-related factors, including ATF5, Chop, and PITRM1. Further investigation revealed that Fundc1 deficiency results in increased cardiomyocyte apoptosis, calcium dysregulation, reduced cell viability, and impaired mitochondrial function, characterized by decreased ATP production, reduced membrane potential, and increased ROS production. Notably, activation of mito-UPR with oligomycin significantly ameliorated these cardiac abnormalities in Fundc1-deficient mice. We identified ATF5 as a key downstream effector of Fundc1, as ATF5 overexpression effectively reversed cardiac dysfunction and restored mito-UPR-related gene expression in Fundc1-deficient hearts. Additionally, we discovered that Fundc1-mediated cardioprotection involves regulation of mitophagy, where its activation improved cardiac function and mitochondrial homeostasis in Fundc1-deficient mice. Our findings reveal a novel Fundc1-ATF5-mito-UPR axis in cardioprotection against high-altitude hypoxia and highlight the crucial role of mitophagy in this protective mechanism, providing new insights into potential therapeutic strategies for high-altitude heart disease.

Keywords:  ATF5; FUNDC1; mito-UPR; mitochondria.

DOI:  https://doi.org/10.7150/ijms.100523
Front Cell Dev Biol. 2024 ;12 1466997

Understanding the impact of ER stress on lung physiology.

Zhiling Fu, Wei Wang, Yuan Gao.

  Human lungs consist of a distinctive array of cell types, which are subjected to persistent challenges from chemical, mechanical, biological, immunological, and xenobiotic stress throughout life. The disruption of endoplasmic reticulum (ER) homeostatic function, triggered by various factors, can induce ER stress. To overcome the elevated ER stress, an adaptive mechanism known as the unfolded protein response (UPR) is activated in cells. However, persistent ER stress and maladaptive UPR can lead to defects in proteostasis at the cellular level and are typical features of the lung aging. The aging lung and associated lung diseases exhibit signs of ER stress-related disruption in cellular homeostasis. Dysfunction resulting from ER stress and maladaptive UPR can compromise various cellular and molecular processes associated with aging. Hence, comprehending the mechanisms of ER stress and UPR components implicated in aging and associated lung diseases could enable to develop appropriate therapeutic strategies for the vulnerable population.

Keywords:  ERstress; aging; autophagy; lung dysfunction; upr

DOI:  https://doi.org/10.3389/fcell.2024.1466997
Sci Rep. 2025 Jan 02. 15(1): 476

MANF overexpression ameliorates oxidative stress-induced apoptosis of human nucleus pulposus cells by facilitating mitophagy through promoting MFN2 expression.

Liang Ma, Xiangyu Meng, Tuerhongjiang Abudurexiti, Yuntao Liu, Jiang Gao, Weibin Sheng.

  Intervertebral disc degeneration (IDD) is a degenerative condition associated with impaired mitophagy. MANF has been shown to promote mitophagy in murine kidneys; however, its role in IDD remains unexplored. This study aimed to elucidate the mechanism by which MANF influences IDD development through the regulation of mitophagy. Human nucleus pulposus (NP) cells were exposed to tert-butyl hydroperoxide (TBHP) to establish an oxidative stress-induced cellular model. The expression levels of MANF in NP cells were quantified using quantitative real-time PCR (qPCR) and Western blotting. The impact of MANF on TBHP-induced NP cells was evaluated by assessing cell viability, apoptosis, and the levels of mitophagy-related proteins. The underlying mechanisms were further investigated using RNA-binding protein immunoprecipitation (RIP), dual-luciferase reporter assays, qPCR, and Western blotting. Results indicated that MANF expression was significantly downregulated in both IDD patients and TBHP-induced NP cells. Overexpression of MANF inhibited apoptosis, enhanced cell viability, and promoted mitophagy in TBHP-treated NP cells. MFN2 was identified as a downstream target of MANF, and MANF overexpression upregulated MFN2 expression in NP cells, whereas TBHP markedly suppressed MFN2 expression. Furthermore, knockdown of MFN2 partially reversed the effects of MANF overexpression on apoptosis, cell viability, and mitophagy in TBHP-treated NP cells. Collectively, these findings demonstrate that MANF overexpression enhances mitophagy by upregulating MFN2 expression, thereby mitigating oxidative stress-induced apoptosis in NP cells. These results provide novel insights into the pathogenesis of IDD.

Keywords:  Intervertebral disc degeneration; MANF; MFN2; Mitophagy

DOI:  https://doi.org/10.1038/s41598-024-84167-9
Theranostics. 2025 ;15(1): 202-215

Big data analytics and scRNA-seq in human aortic aneurysms and dissections: role of endothelial MerTK.

Shijie Liu, Jinzi Wu, Oishani Banerjee, Bingzhong Xue, Hang Shi, Zufeng Ding.

  Rationale: Aortic aneurysms and dissections (AAD) cause more than 10,000 deaths in the United States each year. However, there are no medications that can effectively prevent the pathogenesis of AAD. MER proto-oncogene tyrosine kinase (MerTK) is a key receptor for efferocytosis, a process for the clearance of apoptotic cells. Here, we mainly focused on ascending aortic aneurysms and dissections (AAAD) and investigated the role of endothelial MerTK in AAAD progression. Methods: Single-cell RNA sequencing (scRNA-seq) analysis in human AAAD samples and RNA-seq big data analytics, combined with our unique MerTKflox/flox/Tie2Cre mouse model with MerTK deficiency in endothelial cells (ECs), were applied to define the role of endothelial MerTK in AAAD. Results: Through comparative analyses of scRNA-seq in human AAAD (communications of ECs with other cells) and comprehensive big data analytics including about 600,000 cross analyses, we found that the expression of endothelial MerTK is significantly inhibited in human AAAD, resulting in decreased ability of ECs to engulf antigen presenting cells, phagocytes, leukocytes, blood cells and myeloid cells. Our in vivo data showed a significantly higher incidence of AAAD in MerTK flox/flox/Tie2Cre mice compared to that of their littermate controls of MerTK flox/flox mice (100% vs. 11.1%). MerTK deficiency in ECs induces both endothelial dysfunction and SMC phenotypic alterations, subsequently promoting AAAD development. Conclusions: Our findings indicate that endothelial MerTK impairment and subsequent endothelial dysfunction and SMC phenotypic alterations represent novel mechanisms promoting AAAD.

Keywords:  MerTK; aortic aneurysms and dissections; big data analytics; endothelial cells; scRNA-seq

DOI:  https://doi.org/10.7150/thno.103851
Nat Commun. 2024 Dec 30. 15(1): 10796

Localized molecular chaperone synthesis maintains neuronal dendrite proteostasis.

Célia Alecki, Javeria Rizwan, Phuong Le, Suleima Jacob-Tomas, Mario Fernandez Comaduran, Morgane Verbrugghe, Jia Ming Stella Xu, Sandra Minotti, James Lynch, Jeetayu Biswas, Tad Wu, Heather D Durham, Gene W Yeo, Maria Vera.

Proteostasis is maintained through regulated protein synthesis and degradation and chaperone-assisted protein folding. However, this is challenging in neuronal projections because of their polarized morphology and constant synaptic proteome remodeling. Using high-resolution fluorescence microscopy, we discover that hippocampal and spinal cord motor neurons of mouse and human origin localize a subset of chaperone mRNAs to their dendrites and use microtubule-based transport to increase this asymmetric localization following proteotoxic stress. The most abundant dendritic chaperone mRNA encodes a constitutive heat shock protein 70 family member (HSPA8). Proteotoxic stress also enhances HSPA8 mRNA translation efficiency in dendrites. Stress-mediated HSPA8 mRNA localization to the dendrites is impaired by depleting fused in sarcoma-an amyotrophic lateral sclerosis-related protein-in cultured spinal cord mouse motor neurons or by expressing a pathogenic variant of heterogenous nuclear ribonucleoprotein A2/B1 in neurons derived from human induced pluripotent stem cells. These results reveal a neuronal stress response in which RNA-binding proteins increase the dendritic localization of HSPA8 mRNA to maintain proteostasis and prevent neurodegeneration.

DOI: https://doi.org/10.1038/s41467-024-55055-7