Up-regulation of NOX1/NADPH oxidase following drug-induced myocardial injury promotes cardiac dysfunction and fibrosis

Iwata, Kazuo; Matsuno, Kuniharu; Murata, Ayumi; Zhu, Kai; Fukui, Hitomi; Ikuta, Kazunari; Katsuyama, Masato; Ibi, Masakazu; Matsumoto, Misaki; Ohigashi, Makoto; Wen, Xiaopeng; Zhang, Jia; Yabe‐Nishimura, Chihiro

doi:10.1016/j.freeradbiomed.2018.03.053

Cited by 29 publications

(22 citation statements)

References 37 publications

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“…ROS are well-known for their role in mediating both physiological and pathophysiological signal transduction. In fact, ROS is highly reactive in cardiomyocyte hypertrophy and even in the activation of cardiac fibroblasts 36 . Clinical and experimental studies have provided enough evidences that excess ROS can cause myocardial remodeling, including contractile dysfunction and structural alterations 37 .…”

Section: Discussionmentioning

confidence: 99%

Alpha-lipoic acid protects against pressure overload-induced heart failure via ALDH2-dependent Nrf1-FUNDC1 signaling

Yin

Sun

et al. 2020

Cell Death Dis

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Alpha-lipoic acid (α-LA), a well-known antioxidant, was proved to active ALDH2 in nitrate tolerance and diabetic animal model. However, the therapeutic advantage of α-LA for heart failure and related signaling pathway have not been explored. This study was designed to examine the role of α-LA–ALDH2 in heart failure injury and mitochondrial damage. ALDH2 knockout (ALDH2−/−) mice and primary neonatal rat cardiomyocytes (NRCMs) were subjected to assessment of myocardial function and mitochondrial autophagy. Our data demonstrated α-LA significantly reduced the degree of TAC-induced LV hypertrophy and dysfunction in wild-type mice, not in ALDH2−/− mice. In molecular level, α-LA significantly restored ALDH2 activity and expression as well as increased the expression of a novel mitophagy receptor protein FUNDC1 in wild-type TAC mice. Besides, we confirmed that ALDH2 which was activated by α-LA governed the activation of Nrf1–FUNDC1 cascade. Our data suggest that α-LA played a positive role in protecting the heart against adverse effects of chronic pressure overload.

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Section: Discussionmentioning

confidence: 99%

Alpha-lipoic acid protects against pressure overload-induced heart failure via ALDH2-dependent Nrf1-FUNDC1 signaling

Yin

Sun

et al. 2020

Cell Death Dis

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“…Although fibrosis was previously recognized as an irreversible progress [37], emerging evidence demonstrated that certain circumstances allowed fibrosis resolution when the underlying preventable causes of fibrogenesis were eradicated [38][39][40]. NOX-derived ROS were intimately involved in numerous organ fibrosis such as heart, liver, lung and kidney [41][42][43], particularly for NOX4 in the nephropathic milieu, which was recognized as the most abundant isoforms in renal proximal tubular epithelial cells [29]. A reduction of NOX4 expression by carnosic acid treatment has been proved to protect against unilateral ureteral obstruction-induced renal fibrosis, fueling considerable enthusiasm for NOX4 blockade as an attractive therapy [44].…”

Section: Nox Signalingmentioning

confidence: 99%

Redox signaling in aging kidney and opportunity for therapeutic intervention through natural products

Chen

et al. 2019

Free Radical Biology and Medicine

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Kidney diseases are serious public problems with high morbidity and mortality in the general population and heavily retard renal function with aging regardless of the cause. Although myriad strategies have been assigned to prevent or harness disease progression, unfortunately, thus far, there is a paucity of effective therapies partly due to an insufficient knowledge of underlying pathological mechanisms, indicating deeper studies are urgently needed. Additionally, natural products are increasingly recognized as an alternative source for disease intervention owing to the potent safety and efficacy, which might be exploited for novel drug discovery. In this review, we primarily expatiate the new advances on mediators that might be amenable to targeting aging kidney and kidney diseases, including nicotinamide adenine dinucleotide phosphate oxidase (NOX), transforming growth factor-β (TGF-β), renin-angiotensin system (RAS), nuclear factor-erythroid 2 related factor 2 (Nrf2), peroxisome proliferator-activated γ receptor (PPARγ), advanced glycation endproducts (AGEs) as well as microRNAs and vitagenes. Of note, we conclude by highlighting some natural products which have the potential to facilitate the development of novel treatment for patients with myriad renal diseases.

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“…A, acrolein and MVK dose‐dependently reduced the viability of H9c2 cells. To clarify which NOX isoform(s) is involved in acrolein‐ or MVK‐ induced cytotoxicity, we generated Nox ‐disrupted H9c2 cells by CRISPR–Cas9‐mediated genome editing . Because the expression of NOX2 was marginal in these cells, Nox2 disruption did not affect acrolein‐ or MVK‐induced cytotoxicity (Fig.…”

Section: Resultsmentioning

confidence: 99%

NOX1/NADPH oxidase regulates the expression of multidrug resistance‐associated protein 1 and maintains intracellular glutathione levels

et al. 2019

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The involvement of superoxide‐generating NADPH oxidase (NOX) in the cytotoxic effects of cigarette smoke extracts has been documented. However, the underlying molecular mechanisms and NOX isoform involved have not been fully clarified. Among the different NADPH oxidase isoforms identified so far, NOX1 and NOX4 were found to be expressed in rat H9c2 cardiomyocytes. When H9c2 cells were exposed to acrolein or methyl vinyl ketone (MVK), major toxic components of cigarette smoke extracts, a dose‐dependent decline in cell viability was observed. Unexpectedly, disruption of Nox1 as well as Nox4 significantly exacerbated cytotoxicity induced by acrolein or MVK. Compared with Nox4‐disrupted cells, Nox1‐disrupted cells were more vulnerable to acrolein and MVK at lower concentrations. Disruption of Nox1 markedly attenuated the levels of total and reduced glutathione (GSH) in H9c2 clones. Reduction in the cystine level in the culture medium to deplete intracellular GSH significantly exacerbated acrolein or MVK‐induced cytotoxicity. Nox1 disruption neither attenuated the level of glutamate–cystine antiporter protein nor the activity of glutamate–cysteine ligase, both rate‐limiting factors for GSH synthesis. On the other hand, increased expression of multidrug resistance‐associated protein 1 (MRP1), which mediates glutathione efflux, was demonstrated in Nox1‐disrupted cells. The augmented toxicity of acrolein and MVK in these cells was partially but significantly blunted in the presence of an MRP1 inhibitor, reversan. Taken together, these results show that NOX1/NADPH oxidase regulates the expression of MRP1 to maintain intracellular GSH levels in cardiomyocytes and protect against cytotoxic components of cigarette smoke extracts. A novel crosstalk between NOX1 and MRP1 was demonstrated in this study.

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Up-regulation of NOX1/NADPH oxidase following drug-induced myocardial injury promotes cardiac dysfunction and fibrosis

Cited by 29 publications

References 37 publications

Alpha-lipoic acid protects against pressure overload-induced heart failure via ALDH2-dependent Nrf1-FUNDC1 signaling

Alpha-lipoic acid protects against pressure overload-induced heart failure via ALDH2-dependent Nrf1-FUNDC1 signaling

Redox signaling in aging kidney and opportunity for therapeutic intervention through natural products

NOX1/NADPH oxidase regulates the expression of multidrug resistance‐associated protein 1 and maintains intracellular glutathione levels

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