Physiological and pathological functions of NADPH oxidases during myocardial ischemia–reperfusion

Matsushima, Shouji; Tsutsui, Hiroyuki; Sadoshima, Junichi

doi:10.1016/j.tcm.2014.03.003

Cited by 120 publications

(111 citation statements)

References 24 publications

(31 reference statements)

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“…NADPH oxidase is a critical superoxideproducing source in I/R myocardium and a major component of NADPH oxidase is gp91 phox (Matsushima et al, 2014). As expected, oxidative stress was significantly enhanced in I/R hearts as indicated by increased myocardial superoxide content and gp91 phox expression.…”

Section: Discussionsupporting

confidence: 71%

Punicalagin Pretreatment Attenuates Myocardial Ischemia-Reperfusion Injury via Activation of AMPK

Ding

Sun

et al. 2017

Am. J. Chin. Med.

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Punicalagin (PUN), a major bioactive component in pomegranate juice, has been proven to exert neuroprotective effects against cerebral ischemia/reperfusion (I/R) insult via anti-oxidant properties. This study aims to investigate whether PUN provides cardioprotection against myocardial I/R (MI/R) injury and the underlying mechanisms. PUN (30 mg/ kg/d) or vehicle was intragastrically administered to Sprague-Dawley rats for one week before the operation. MI/R was induced by ligating the left anterior descending coronary artery for 30 min and subsequent reperfusion for 3 h. PUN pretreatment conferred cardioprotective effects against MI/R injury by improving cardiac function, limiting infarct size, reducing serum creatine kinase-MB and lactate dehydrogenase activities, and suppressing cardiomyocyte apoptosis. Moreover, PUN pretreatment inhibited I/R-induced myocardial oxidative stress as evidenced by decreased generation of superoxide content and

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Section: Discussionsupporting

confidence: 71%

Punicalagin Pretreatment Attenuates Myocardial Ischemia-Reperfusion Injury via Activation of AMPK

Ding

Sun

et al. 2017

Am. J. Chin. Med.

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“…Nox2 is associated with the plasma membrane, and Nox4 is associated predominantly with organelle membranes. Overall, Nox2 and Nox4 have been shown to be important and equal contributors of ROS in myocardial ischemia/reperfusion (Matsushima et al 2014). LPS is commonly used to model sepsis, and several researchers have found that TLR4 has a role in LPSmediated increased ROS and cell death.…”

Section: Discussionmentioning

confidence: 99%

TLR4 mutation and HSP60-induced cell death in adult mouse cardiac myocytes

Heiserman

Chen

Kim

et al. 2015

Cell Stress and Chaperones

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Extracellular (ex) HSP60 is increasingly recognized as an agent of cell injury. Previously, we reported that low endotoxin exHSP60 causes cardiac myocyte apoptosis. Our findings supported a role for Toll-like receptor (TLR) 4 in HSP60 mediated apoptosis. To further investigate the involvement of TLR4 in cardiac injury, we studied adult cardiac myocytes from C3H/HeJ (HeJ) mice, which have a mutant, nonfunctional TLR4, and compared the results with parallel studies using wild-type (WT) mice. Nuclear factor κB (NFκB) activation is an early step downstream of TLR4. NFκB was activated 1 h after treatment with HSP60 in WT, but not HeJ mouse myocytes. ExHSP60 caused apoptosis in cardiac myocytes from WT mice, but not in myocytes from the HeJ mutants. To further elucidate the importance of exHSP60 in cardiac myocyte injury, both WT and HeJ mutant isolated mouse adult cardiac myocytes were exposed to hypoxia/reoxygenation. Anti-HSP60 antibody treatment reduced apoptosis in the WT group, but had no effect on the HeJ mutant myocytes. Unexpectedly, necrosis was also decreased in the HeJ mutants. Necrosis after hypoxia/reoxygenation in WT cardiac myocytes was mediated in part by TLR2 and TLR4 through rapid activation of PKCα, followed by increased expression of Nox2, and this was ameliorated by blocking antibodies to TLR2/4. These studies provide further evidence that TLR4 mediates exHSP60-associated apoptosis and that exHSP60 has an important role in cardiac myocyte injury, both apoptotic and necrotic.

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“…The accumulation of ROS leads to cellular IR oxidative injury (such as apoptosis or necrosis) through direct effects (such as lipid peroxidation) or indirect effects (such as activation of the redox signaling pathways) [11,28]. Although multiple sources of ROS have been reported, evidence suggests NOX as a major contributor to ROS generation in myocardium during IR [14,19]. Among the 7 isoforms, NOX3 is highly expressed in the cochlea [2]; Duox-1 and Duox-2 are predominantly expressed in epithelial cells [31]; NOX1, NOX2 and NOX4 are expressed in cardiovascular systems while NOX5 was absent from the rodent (rat, mouse) genomes [7].…”

Section: Discussionmentioning

confidence: 99%

“…The main reason for choosing these two models is because NOX2 expression has been reported to be significantly upregulated following myocardial IR or HR, and inhibition of MLCK or NOX is able to attenuate IR or HR injury [17,19]. In the present study, we confirmed a marked elevation of nuclear p-MYL2 level in myocardium following IR, accompanied by increased NOX2 expression (mRNA and protein), NOX2 products (H 2 O 2 ) and myocardial injury (infarct size, CK release and apoptosis); these phenomena were attenuated, at least partially, by inhibition of MLCK.…”

Section: Discussionmentioning

confidence: 99%

“…Among these isoforms, NOX2 and NOX4 are abundantly expressed in cardiomyocytes, and play a key role in mediation of cardiac oxidative injury and Electronic supplementary material The online version of this article (doi:10.1007/s00395-015-0494-5) contains supplementary material, which is available to authorized users. remodeling under various pathological conditions [7,19]. NOX4 is believed to be constitutively expressed and is essential for the development of cardiac hypertrophy [1].…”

Section: Introductionmentioning

confidence: 99%

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Nuclear cardiac myosin light chain 2 modulates NADPH oxidase 2 expression in myocardium: a novel function beyond muscle contraction

et al. 2015

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Recent studies demonstrated that NADPH oxidase 2 (NOX2) expression in myocardium after ischemia-reperfusion (IR) is significantly upregulated. However, the underlying mechanisms remain unknown. This study aims to determine if nuclear cardiac myosin light chain 2 (MYL2), a well-known regulatory subunit of myosin, functions as a transcription factor to promote NOX2 expression following myocardial IR in a phosphorylation-dependent manner. We examined the phosphorylation status of nuclear MYL2 (p-MYL2) in a rat model of myocardial IR (left main coronary artery subjected to 1 h ligation and 3 h reperfusion) injury, which showed IR injury and upregulated NOX2 expression as expected, accompanied by elevated H₂O₂ and nuclear p-MYL2 levels; these effects were attenuated by inhibition of myosin light chain kinase (MLCK). Next, we explored the functional relationship of nuclear p-MYL2 with NOX2 expression in H9c2 cell model of hypoxia-reoxygenation (HR) injury. In agreement with our in vivo findings, HR treatment increased apoptosis, NOX2 expression, nuclear p-MYL2 and H₂O₂ levels, and the increases were ameliorated by inhibition of MLCK or knockdown of MYL2. Finally, molecular biology techniques including co-immunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP), DNA pull-down and luciferase reporter gene assay were utilized to decipher the molecular mechanisms. We found that nuclear p-MYL2 binds to the consensus sequence AGCTCC in NOX2 gene promoter, interacts with RNA polymerase II and transcription factor IIB to form a transcription preinitiation complex, and thus activates NOX2 gene transcription. Our results demonstrate that nuclear MYL2 plays an important role in IR injury by transcriptionally upregulating NOX2 expression to enhance oxidative stress in a phosphorylation-dependent manner.

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Physiological and pathological functions of NADPH oxidases during myocardial ischemia–reperfusion

Cited by 120 publications

References 24 publications

Punicalagin Pretreatment Attenuates Myocardial Ischemia-Reperfusion Injury via Activation of AMPK

Punicalagin Pretreatment Attenuates Myocardial Ischemia-Reperfusion Injury via Activation of AMPK

TLR4 mutation and HSP60-induced cell death in adult mouse cardiac myocytes

Nuclear cardiac myosin light chain 2 modulates NADPH oxidase 2 expression in myocardium: a novel function beyond muscle contraction

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