NADPH Oxidases in Heart Failure: Poachers or Gamekeepers?

Zhang, Min; Perino, Alessia; Ghigo, Alessandra; Hirsch, Emilio; Shah, Ajay M.

doi:10.1089/ars.2012.4550

Cited by 175 publications

(171 citation statements)

References 226 publications

(218 reference statements)

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“…While this stretch response may be the physiologic function of cardiac NOX2, long-term activation of NOX2 may be maladaptive since it promotes arrhythmia (36) and heart failure (37). Previous work has demonstrated that sepsis increases sarcoplasmic reticulum calcium leak (sparks) in cardiomyocytes (23).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of NADPH oxidase 2 (NOX2) prevents sepsis-induced cardiomyopathy by improving calcium handling and mitochondrial function

et al. 2017

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Section: Discussionmentioning

confidence: 99%

Inhibition of NADPH oxidase 2 (NOX2) prevents sepsis-induced cardiomyopathy by improving calcium handling and mitochondrial function

et al. 2017

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“…Nox4 is frequently alleged to predominantly generate hydrogen peroxide rather than superoxide (48)(49)(50)(51)(52). This property of the oxidase may have important implications for the interaction with NO signaling, since hydrogen peroxide, unlike superoxide, does not react with NO to form peroxynitrite and may even stimulate eNOS activity (49,(51)(52)(53)(54).…”

Section: Discussionmentioning

confidence: 99%

“…This property of the oxidase may have important implications for the interaction with NO signaling, since hydrogen peroxide, unlike superoxide, does not react with NO to form peroxynitrite and may even stimulate eNOS activity (49,(51)(52)(53)(54). Hence, it was recently described that Nox4 enhances eNOS activity and NO signaling (52)(53)(54). Consistent with these observations, the Nox oxidases that have been linked to eNOS uncoupling in vascular pathology, including diabetes, are the superoxide-generating isoforms Nox1 and Nox2 (also known as gp91 phox ) (55)(56)(57)(58).…”

Section: Discussionmentioning

confidence: 99%

Sestrin 2 and AMPK Connect Hyperglycemia to Nox4-Dependent Endothelial Nitric Oxide Synthase Uncoupling and Matrix Protein Expression

Eid

Lee

Roman

et al. 2013

Molecular and Cellular Biology

123

121

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Mesangial matrix accumulation is an early feature of glomerular pathology in diabetes. Oxidative stress plays a critical role in hyperglycemia-induced glomerular injury. Here, we demonstrate that, in glomerular mesangial cells (MCs), endothelial nitric oxide synthase (eNOS) is uncoupled upon exposure to high glucose (HG), with enhanced generation of reactive oxygen species (ROS) and decreased production of nitric oxide. Peroxynitrite mediates the effects of HG on eNOS dysfunction. HG upregulates Nox4 protein, and inhibition of Nox4 abrogates the increase in ROS and peroxynitrite generation, as well as the eNOS uncoupling triggered by HG, demonstrating that Nox4 functions upstream from eNOS. Importantly, this pathway contributes to HGinduced MC fibronectin accumulation. Nox4-mediated eNOS dysfunction was confirmed in glomeruli of a rat model of type 1 diabetes. Sestrin 2-dependent AMP-activated protein kinase (AMPK) activation attenuates HG-induced MC fibronectin synthesis through blockade of Nox4-dependent ROS and peroxynitrite generation, with subsequent eNOS uncoupling. We also find that HG negatively regulates sestrin 2 and AMPK, thereby promoting Nox4-mediated eNOS dysfunction and increased fibronectin. These data identify a protective function for sestrin 2/AMPK and potential targets for intervention to prevent fibrotic injury in diabetes.T he pathological manifestations of early diabetes in the glomerular microvascular bed include glomerular mesangial cell hypertrophy associated with an increase in mesangial matrix accumulation (1, 2). These events precede the development of irreversible glomerulosclerosis (1, 2). Data from animal models of diabetes, as well as from cultured cells, indicate that hyperglycemia and high glucose (HG) increase extracellular matrix expansion in mesangial cells (MCs) (1, 2).Oxidative stress with increased generation of reactive oxygen species (ROS) has emerged as a critical pathogenic factor in the development of diabetic nephropathy (DN) (1-3). However, the protective effects of traditional antioxidants are very limited. Identifying sources of ROS should help in designing rational therapy to modulate oxidative stress. Although multiple pathways may result in ROS generation, numerous studies identified NADPH oxidases of the Nox family as major sources of ROS in various nonphagocytic/stromal cells, including most kidney cells (4-6). Evidence from studies in cultured cells suggests that the isoform Nox4 is required for the damaging effects of HG that contribute to microvascular complications of diabetes in the retina, the heart, or the kidney (7-13). We have previously reported that Nox4-dependent ROS generation mediates glomerular hypertrophy and mesangial matrix accumulation in early type 1 diabetes (13). In MCs, we showed that Nox4-derived ROS result in the increased fibronectin expression induced by HG (13,14). Nevertheless, the mechanisms that Nox4 utilizes to exert this biological effect remain unclear, and the upstream regulators or downstream effectors of the oxidase are n...

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“…However, the fact that Nox4 produces more hydrogen peroxide than superoxide compared with other Nox oxidases (12, 50 -54) cannot be ignored. As a consequence, because hydrogen peroxide, unlike superoxide, does not react with NO, Nox4 is generally considered to be unlikely to significantly contribute to peroxynitrite generation and NOS uncoupling (51,(53)(54)(55)(56). This is reinforced by the recent observations that Nox4-derived hydrogen peroxide enhances eNOS activity and NO signaling.…”

Section: Discussionmentioning

confidence: 99%

Nox4 NADPH Oxidase Mediates Peroxynitrite-dependent Uncoupling of Endothelial Nitric-oxide Synthase and Fibronectin Expression in Response to Angiotensin II

Lee¹,

Wauquier²,

Eid³

et al. 2013

Journal of Biological Chemistry

115

105

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Background: Oxidative stress is critical for the fibrotic response of mesangial cells (MCs) to angiotensin II. Results: Nox4-and mitochondrial reactive oxygen species (ROS)-dependent endothelial nitric-oxide synthase (eNOS) uncoupling led to fibronectin accumulation in MCs stimulated by angiotensin II. Conclusion: The Nox4/mitochondrial ROS/eNOS pathway mediates angiotensin II-induced MC injury. Significance: Targeting Nox4 and mitochondrial ROS is a promising therapeutic approach.

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NADPH Oxidases in Heart Failure: Poachers or Gamekeepers?

Cited by 175 publications

References 226 publications

Inhibition of NADPH oxidase 2 (NOX2) prevents sepsis-induced cardiomyopathy by improving calcium handling and mitochondrial function

Inhibition of NADPH oxidase 2 (NOX2) prevents sepsis-induced cardiomyopathy by improving calcium handling and mitochondrial function

Sestrin 2 and AMPK Connect Hyperglycemia to Nox4-Dependent Endothelial Nitric Oxide Synthase Uncoupling and Matrix Protein Expression

Nox4 NADPH Oxidase Mediates Peroxynitrite-dependent Uncoupling of Endothelial Nitric-oxide Synthase and Fibronectin Expression in Response to Angiotensin II

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