bims-noxint 2021-12-05 papers

Issue of 2021‒12‒05
five papers selected by
Laia Caja Puigsubira
Uppsala University

Antioxid Redox Signal. 2021 Dec 03.

Nox, Nox, Are You There? The Role of NADPH Oxidases in the Peripheral Nervous System.

Stephanie A Eid, Masha G Savelieff, Assaad Antoine Eid, Eva L Feldman.

SIGNIFICANCE: Reactive oxygen species (ROS) contribute to multiple aspects of peripheral nervous system (PNS) biology ranging from physiological processes (e.g. axonal outgrowth and regeneration), to pathophysiology (e.g. nerve degeneration). Although ROS are derived from multiple sources, NADPH oxidase (Nox) family members are dedicated to ROS generation. Noxs are expressed in the PNS and their overexpression is associated with detrimental effects on nerve function and contribute, at least in part, to peripheral neuropathies. Recent Advances: Of the 7 members, studies mostly focused on Nox1, Nox2, and Nox4, which are expressed in the PNS in a cell-specific manner. We have also recently identified human Nox5 in sural nerve biopsies. When maintained at homeostatic levels, Noxs regulate several aspects of peripheral nerve health, most notably neurite outgrowth and axonal regeneration following nerve lesion. While Nox2 and Nox4 dysregulation is a major source of oxidative stress in PNS disorders, including neuropathic pain and diabetic peripheral neuropathy, recent evidence also implicates Nox1 and Nox5.CRITICAL ISSUES: Although there is compelling evidence for a direct role of Noxs on nerve function, little is known about their subcellular localization, intercellular regulation, and interaction. These, together with redox signaling, are considered crucial components of nerve redox status. Additionally, the lack of isoform-specific inhibitors limits conclusions about the physiological role of Noxs in the PNS and their therapeutic potential in peripheral neuropathies.
FUTURE DIRECTIONS: Future research using isoform-specific genetic and pharmacological approaches are therefore needed to better understand the significance of Nox enzymes in PNS (patho) physiology.

DOI: https://doi.org/10.1089/ars.2021.0135

Biochem Pharmacol. 2021 Nov 26. pii: S0006-2952(21)00485-8. [Epub ahead of print] 114859

CCR5 antagonist treatment inhibits vascular injury by regulating NADPH oxidase 1.

Shubhnita Singh, Ariane Bruder-Nascimento, Eric J Belin de Chantemele, Thiago Bruder-Nascimento.

BACKGROUND: Chemokine (C- Cmotif) ligand 5 (CCL5) and its receptor C-C motif chemokine receptor 5 (CCR5), have been broadly studied in conjunction with infectious pathogens, however, their involvement in cardiovascular disease is not completely understood. NADPH oxidases (Noxs) are the major source of reactive oxygen species (ROS) in the vasculature. Whether the activation of Noxs is CCL5/CCR5 sensitive and whether such interaction initiates vascular injury is unknown. We investigated whether CCL5/CCR5 leads to vascular damage by activating Noxs.MATERIAL AND METHODS: We used rat aortic smooth muscle cells (RASMC) to investigate the molecular mechanisms by which CCL5 leads to vascular damage and carotid ligation (CL) to analyze the effects of blocking CCR5 on vascular injury.
RESULTS: CCL5 induced Nox1 expression in concentration and time-dependent manners, with no changes in Nox2 or Nox4. Maraviroc pre-treatment (CCR5 antagonist, 40uM) blunted CCL5-induced Nox1 expression. Furthermore, CCL5 incubation led to ROS production and activation of Erk1/2 and NFkB, followed by increased vascular cell migration, proliferation, and inflammatory markers. Notably, Nox1 inhibition (GKT771, 10uM) blocked CCL5-dependent effects. In vivo, CL induced pathological vascular remodeling and inflammatory genes and increased Nox1 and CCR5 expression. Maraviroc treatment (25mg/Kg/day) reduced pathological vascular growth and Nox1 expression.
CONCLUSIONS: Our findings suggest that CCL5 activates Nox1 in the vasculature, leading to vascular injury likely via NFkB and Erk1/2. Herein, we place CCR5 antagonists and/or Nox1 inhibitors might be preeminent antiproliferative compounds to reduce the cardiovascular risk associated with medical procedures (e.g. angioplasty) and vascular diseases associated with vascular hyperproliferation.

Keywords: CCL5; CCR5; Nox1; Reactive Oxygen Species; Vascular

DOI: https://doi.org/10.1016/j.bcp.2021.114859

J Cardiovasc Pharmacol. 2021 Nov 23.

Pharmacological inhibition of mTOR attenuates DOCA-salt-induced hypertension and related pathophysiology: regulation of oxidative stress, inflammation and cardiovascular hypertrophy in male rats.

Meryem Temiz-Resitoglu, Demet Sinem Guden, Sefika Pinar Senol, Ozden Vezir, Nehir Sucu, Deniz Kibar, Sakir Necat Yılmaz, Bahar Tunctan, Kafait U Malik, Seyhan Sahan-Firat.

ABSTRACT: The present study aimed to explore the contribution of mTOR in deoxycorticosterone acetate (DOCA)-salt-induced hypertension and related pathophysiological changes in cardiovascular and renal tissues. DOCA-salt loading resulted in an increase in systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean blood pressure (MBP) along with the activity of ribosomal protein S6 (rpS6), the effector protein of mTOR. Treatment with rapamycin, the selective inhibitor of mTOR, initiated at the 4th week of DOCA-salt administration normalized the SBP and attenuated rpS6 activity in the heart, aorta, and kidney. Cardiac and vascular hypertrophy, oxidative stress, and infiltration of macrophages (CD68+), the marker of inflammation, were also reduced in rapamycin-treated DOCA-salt hypertensive rats. In addition, renal hypertrophy and dysfunction were also reduced with rapamycin-treated hypertensive rats. Moreover, these pathophysiological changes in DOCA-salt hypertensive rats were associated with increased NADPH oxidase (NOX) activity, gp91phox (formerly NOX2) expression, ERK1/2, and p38 MAPK activities in the heart, aorta, and kidney were minimized by rapamycin. These data indicate that mTOR plays an important role in regulating blood pressure and the development of cardiovascular and renal pathophysiological changes, most likely due to increased NOX expression/activity, ERK1/2, and p38 MAPK activity with macrophages infiltration in the heart, kidney, and aorta. Pharmacological inhibition of mTOR and related signaling pathways could serve as a novel target for the treatment of hypertension.

DOI: https://doi.org/10.1097/FJC.0000000000001187

J Cell Mol Med. 2021 Nov 29.

CaMKII inhibitor KN-93 impaired angiogenesis and aggravated cardiac remodelling and heart failure via inhibiting NOX2/mtROS/p-VEGFR2 and STAT3 pathways.

Yajuan Ni, Jie Deng, Hongyuan Bai, Chang Liu, Xin Liu, Xiaofang Wang.

Persistent cardiac Ca2+ /calmodulin-dependent Kinase II (CaMKII) activation was considered to promote heart failure (HF) development, some studies believed that CaMKII was a target for therapy of HF. However, CaMKII was an important mediator for the ischaemia-induced coronary angiogenesis, and new evidence confirmed that angiogenesis inhibited cardiac remodelling and improved heart function, and some conditions which impaired angiogenesis aggravated ventricular remodelling. This study aimed to investigate the roles and the underlying mechanisms of CaMKII inhibitor in cardiac remodelling. First, we induced cardiac remodelling rat model by ISO, pre-treated by CaMKII inhibitor KN-93, evaluated heart function by echocardiography measurements, and performed HE staining, Masson staining, Tunel staining, Western blot and RT-PCR to test cardiac remodelling and myocardial microvessel density; we also observed ultrastructure of cardiac tissue with transmission electron microscope. Second, we cultured HUVECs, pre-treated by ISO and KN-93, detected cell proliferation, migration, tubule formation and apoptosis, and carried out Western blot to determine the expression of NOX2, NOX4, VEGF, VEGFR2, p-VEGFR2 and STAT3; mtROS level was also measured. In vivo, we found KN-93 severely reduced myocardial microvessel density, caused apoptosis of vascular endothelial cells, enhanced cardiac hypertrophy, myocardial apoptosis, collagen deposition, aggravated the deterioration of myocardial ultrastructure and heart function. In vitro, KN-93 inhibited HUVECs proliferation, migration and tubule formation, and promoted apoptosis of HUVECs. The expression of NOX2, NOX4, p-VEGFR2 and STAT3 were down-regulated by KN-93; mtROS level was severely reduced by KN-93. We concluded that KN-93 impaired angiogenesis and aggravated cardiac remodelling and heart failure via inhibiting NOX2/mtROS/p-VEGFR2 and STAT3 pathways.

Keywords: CaMKII; KN-93; angiogenesis; cardiac remodelling; heart failure

DOI: https://doi.org/10.1111/jcmm.17081

Cardiovasc Res. 2021 Nov 26. pii: cvab349. [Epub ahead of print]

NOX1 mediates metabolic heart disease in mice and is upregulated in monocytes of humans with diastolic dysfunction.

Lifen Xu, Melania Balzarolo, Emma L Robinson, Vera Lorenz, Giacomo Della Verde, Lydia Joray, Michika Mochizuki, Beat A Kaufmann, Gideon Valstar, Saskia C A de Jager, Hester M den Ruijter, Stephane Heymans, Otmar Pfister, Gabriela M Kuster.

AIMS: Microvascular inflammation plays an important role in the pathogenesis of diastolic dysfunction (DD) and metabolic heart disease. NOX1 is expressed in vascular and immune cells and has been implicated in the vascular pathology of metabolic disease. However, its contribution to metabolic heart disease is less understood.METHODS AND RESULTS: NOX1-deficient mice (KO) and male wild-type (WT) littermates were fed a high-fat high-sucrose diet (HFHS) and injected streptozotocin (75 mg/kg i.p.) or control diet (CTD) and sodium citrate. Despite similar weight gain and increase in fasting blood glucose and insulin, only WT-HFHS but not KO-HFHS mice developed concentric cardiac hypertrophy and elevated left ventricular filling pressure. This was associated with increased endothelial adhesion molecule expression, accumulation of Mac-2-, IL-1β- and NLRP3-positive cells and nitrosative stress in WT-HFHS but not KO-HFHS hearts. Nox1 mRNA was solidly expressed in CD45+ immune cells isolated from healthy mouse hearts, but was negligible in cardiac CD31+ endothelial cells. However, in vitro, Nox1 expression increased in response to LPS in endothelial cells and contributed to LPS-induced upregulation of Icam-1. Nox1 was also upregulated in mouse bone marrow-derived macrophages in response to LPS. In peripheral monocytes from age- and sex-matched symptomatic patients with and without DD, NOX1 was significantly higher in patients with DD compared to those without DD.
CONCLUSIONS: NOX1 mediates endothelial activation and contributes to myocardial inflammation and remodeling in metabolic disease in mice. Given its high expression in monocytes of humans with DD, NOX1 may represent a potential target to mitigate heart disease associated with DD.
TRANSLATIONAL PERSPECTIVE: In their multifactorial pathogenesis, diastolic dysfunction (DD) and heart failure with preserved ejection fraction (HFpEF) still remain poorly understood. They frequently occur in patients with obesity and metabolic syndrome. Microvascular inflammation and dysfunction have recently been recognized as major driving forces. We show that genetic deletion of Nox1 prevents cardiac inflammation, remodeling and dysfunction in metabolic disease in mice and find NOX1 upregulated in peripheral monocytes of patients with DD. These findings add to our understanding how obesity, inflammation and heart disease are linked, which is a prerequisite to find therapeutic strategies beyond the control of co-morbidities in HFpEF.

Keywords: Diastolic dysfunction; NOX1; hypertrophy; inflammation; metabolic heart disease

DOI: https://doi.org/10.1093/cvr/cvab349