Both cardiomyocyte and endothelial cell Nox4 mediate protection against hemodynamic overload-induced remodelling

Zhang, Min; Mongue‐Din, Héloïse; Martin, Daniel; Catibog, Norman; Smyrnias, Ioannis; Zhang, Xiaohong; Yu, Bin; Wang, Minshu; Brandes, Ralf P.; Schröder, Katrin; Shah, Ajay M.

doi:10.1093/cvr/cvx204

Cited by 57 publications

(50 citation statements)

References 25 publications

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“…We showed that the Nox4 expression in the heart of diabetic rats was upregulated while SPR treatment decreased the expression. Interestingly, a recent study showed that Nox4, expressed in both cardiomyocyte and endothelial cells, mediated the protection against hemodynamic overload-induced cardiac remodeling [ 63 ]. The discrepancy between this research and ours may be due to different rodent models.…”

Section: Discussionmentioning

confidence: 99%

Spironolactone Protects against Diabetic Cardiomyopathy in Streptozotocin-Induced Diabetic Rats

Liu

Gong

et al. 2018

Journal of Diabetes Research

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Spironolactone (SPR) has been shown to protect diabetic cardiomyopathy (DCM), but the specific mechanisms are not fully understood. Here, we determined the cardioprotective role of SPR in diabetic mice and further explored the potential mechanisms in both in vivo and in vitro models. Streptozotocin- (STZ-) induced diabetic rats were used as the in vivo model. After the onset of diabetes, rats were treated with either SPR (STZ + SPR) or saline (STZ + NS) for 12 weeks; nondiabetic rats were used as controls (NDCs). In vitro, H9C2 cells were exposed to aldosterone, with or without SPR. Cardiac structure was investigated with transmission electron microscopy and pathological examination; immunohistochemistry was performed to detect nitrotyrosine, collagen-1, TGF-β1, TNF-α, and F4/80 expression; and gene expression of markers for oxidative stress, inflammation, fibrosis, and energy metabolism was detected. Our results suggested that SPR attenuated mitochondrial morphological abnormalities and sarcoplasmic reticulum enlargement in diabetic rats. Compared to the STZ + NS group, cardiac oxidative stress, fibrosis, inflammation, and mitochondrial dysfunction were improved by SPR treatment. Our study showed that SPR had cardioprotective effects in diabetic rats by ameliorating mitochondrial dysfunction and reducing fibrosis, oxidative stress, and inflammation. This study, for the first time, indicates that SPR might be a potential treatment for DCM.

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Section: Discussionmentioning

confidence: 99%

Spironolactone Protects against Diabetic Cardiomyopathy in Streptozotocin-Induced Diabetic Rats

Liu

Gong

et al. 2018

Journal of Diabetes Research

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“…Nox4 is highly expressed in the kidney and in osteoclasts, fibroblasts, cardiomyocytes, endothelial and vascular smooth muscle cells (Yang et al, 2018;Zhang et al, 2018). It is also abundant in tumour cells and has been considered an oncoprotein (Graham et al, 2010).…”

Section: A Primer On Nox Isoformsmentioning

confidence: 99%

NOX5: Molecular biology and pathophysiology

Touyz

Anagnostopoulou

Ríos

et al. 2019

Experimental Physiology

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New Findings What is the topic of this review? This review provides a comprehensive overview of Nox5 from basic biology to human disease and highlights unique features of this Nox isoform What advances does it highlight? Major advances in Nox5 biology relate to crystallization of the molecule and new insights into the pathophysiological role of Nox5. Recent discoveries have unravelled the crystal structure of Nox5, the first Nox isoform to be crystalized. This provides new opportunities to develop drugs or small molecules targeted to Nox5 in an isoform‐specific manner, possibly for therapeutic use. Moreover genome wide association studies (GWAS) identified Nox5 as a new blood pressure‐associated gene and studies in mice expressing human Nox5 in a cell‐specific manner have provided new information about the (patho) physiological role of Nox5 in the cardiovascular system and kidneys. Nox5 seems to be important in the regulation of vascular contraction and kidney function. In cardiovascular disease and diabetic nephropathy, Nox5 activity is increased and this is associated with increased production of reactive oxygen species and oxidative stress implicated in tissue damage. Abstract Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox), comprise seven family members (Nox1–Nox5 and dual oxidase 1 and 2) and are major producers of reactive oxygen species in mammalian cells. Reactive oxygen species are crucially involved in cell signalling and function. All Noxs share structural homology comprising six transmembrane domains with two haem‐binding regions and an NADPH‐binding region on the intracellular C‐terminus, whereas their regulatory systems, mechanisms of activation and tissue distribution differ. This explains the diverse function of Noxs. Of the Noxs, NOX5 is unique in that rodents lack the gene, it is regulated by Ca 2+ , it does not require NADPH oxidase subunits for its activation, and it is not glycosylated. NOX5 localizes in the perinuclear and endoplasmic reticulum regions of cells and traffics to the cell membrane upon activation. It is tightly regulated through numerous post‐translational modifications and is activated by vasoactive agents, growth factors and pro‐inflammatory cytokines. The exact pathophysiological significance of NOX5 remains unclear, but it seems to be important in the physiological regulation of sperm motility, vascular contraction and lymphocyte differentiation, and NOX5 hyperactivation has been implicated in cardiovascular disease, kidney injury and cancer. The field of NOX5 biology is still in its infancy, but with new insights into its biochemistry and cellular regulation, discovery of the NOX5 crystal structure and genome‐wide association studies implicating NOX5 in disease, the time is now ripe to advance NOX5 research. This review provides a comprehensive overview of our current understanding of NOX5, from basic ...

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“…Elevated activity of catalase (Figure 8 B) is especially interesting, since cardiac-specific overexpression of catalase has been shown to abolish oxidative stress and prevent the progression to overt HF in an alternative Gαq-overexpressing transgenic mouse model ( 70 ). On the other hand, Nox4-derived hydrogen peroxide both in cardiomyocytes and endothelial cells was shown to mediate protection against pressure overload cardiac remodeling ( 71 ). Our analysis showed that increased activity of CAT was associated with elevated activity of GPx, which overexpression in mice was previously shown to prevent left ventricular failure after myocardial infarction ( 72 ).…”

Section: Discussionmentioning

confidence: 99%

Immuno-Spin Trapping-Based Detection of Oxidative Modifications in Cardiomyocytes and Coronary Endothelium in the Progression of Heart Failure in Tgαq*44 Mice

Proniewski

Czarny

Хомич³

et al. 2018

Front. Immunol.

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Recent studies suggest both beneficial and detrimental role of increased reactive oxygen species and oxidative stress in heart failure (HF). However, it is not clear at which stage oxidative stress and oxidative modifications occur in the endothelium in relation to cardiomyocytes in non-ischemic HF. Furthermore, most methods used to date to study oxidative stress are either non-specific or require tissue homogenization. In this study, we used immuno-spin trapping (IST) technique with fluorescent microscopy-based detection of DMPO nitrone adducts to localize and quantify oxidative modifications of the hearts from Tgαq*44 mice; a murine model of HF driven by cardiomyocyte-specific overexpression of Gαq* protein. Tgαq*44 mice and age-matched FVB controls at early, transition, and late stages of HF progression were injected with DMPO in vivo and analyzed ex vivo for DMPO nitrone adducts signals. Progressive oxidative modifications in cardiomyocytes, as evidenced by the elevation of DMPO nitrone adducts, were detected in hearts from 10- to 16-month-old, but not in 8-month-old Tgαq*44 mice, as compared with age-matched FVB mice. The DMPO nitrone adducts were detected in left and right ventricle, septum, and papillary muscle. Surprisingly, significant elevation of DMPO nitrone adducts was also present in the coronary endothelium both in large arteries and in microcirculation simultaneously, as in cardiomyocytes, starting from 10-month-old Tgαq*44 mice. On the other hand, superoxide production in heart homogenates was elevated already in 6-month-old Tgαq*44 mice and progressively increased to high levels in 14-month-old Tgαq*44 mice, while the enzymatic activity of catalase, glutathione reductase, and glutathione peroxidase was all elevated as early as in 4-month-old Tgαq*44 mice and stayed at a similar level in 14-month-old Tgαq*44. In summary, this study demonstrates that IST represents a unique method that allows to quantify oxidative modifications in cardiomyocytes and coronary endothelium in the heart. In Tgαq*44 mice with slowly developing HF, driven by cardiomyocyte-specific overexpression of Gαq* protein, an increase in superoxide production, despite compensatory activation of antioxidative mechanisms, results in the development of oxidative modifications not only in cardiomyocytes but also in coronary endothelium, at the transition phase of HF, before the end-stage disease.

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Both cardiomyocyte and endothelial cell Nox4 mediate protection against hemodynamic overload-induced remodelling

Cited by 57 publications

References 25 publications

Spironolactone Protects against Diabetic Cardiomyopathy in Streptozotocin-Induced Diabetic Rats

Spironolactone Protects against Diabetic Cardiomyopathy in Streptozotocin-Induced Diabetic Rats

NOX5: Molecular biology and pathophysiology

Immuno-Spin Trapping-Based Detection of Oxidative Modifications in Cardiomyocytes and Coronary Endothelium in the Progression of Heart Failure in Tgαq*44 Mice

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