Cardiac-specific overexpression of metallothionein attenuates myocardial remodeling and contractile dysfunction in l-NAME-induced experimental hypertension: Role of autophagy regulation

Yang, Lifang; Gao, Jianyuan; Ma, Jie; Xu, Xihui; Wang, Qiurong; Xiong, Lize; Ren, Jun

doi:10.1016/j.toxlet.2015.06.005

Cited by 31 publications

(20 citation statements)

References 70 publications

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“…Our finding is consistent with earlier notion that antioxidants can attenuate cardiac dysfunction in hypertension . Moreover, our recent study revealed that metallothionein can protect heart from L‐NAME‐induced cardiac dysfunction in experimental hypertension through autophagy regulation . Our data shown here are in favour of the notion that hypertension may impair redox balance and mitochondria function in myocardium, which leads to apoptotic cell death, inflammation and cardiac dysfunction.…”

Section: Discussionsupporting

confidence: 93%

“…[14][15][16][17] In addition, data from our group suggested that metallothionein also preserved cardiac function via autophagy inhibition in cardiac dysfunction resulted from N G -nitro-L-arginine methyl ester hydrochloride (L-NAME)-induced hypertension. 18 Hence, the NO synthase inhibitor L-NAME was employed to generate experimental hypertensive model. 19,20 To discern the role of macrophage infiltration, inflammation, oxidative stress, apoptosis in metallothionein-and hypertensioninduced cardiac dysfunction, levels of macrophage infiltration marker F4/80, inflammation marker interleukin-1β (IL-1β), superoxide (O − 2 ) production and apoptotic markers Bax, bcl-2, phosphorylated BAD, Caspase 9 and Caspase 12 and cleaved Caspase 3 were evaluated in wild-type and metallothionein transgenic mice treated with L-NAME.…”

Section: Introductionmentioning

confidence: 99%

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Cardiac‐specific overexpression of metallothionein attenuates L‐NAME‐induced myocardial contractile anomalies and apoptosis

Yang

Tan

et al. 2019

J Cellular Molecular Medi

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Hypertension contributes to the high cardiac morbidity and mortality. Although oxidative stress plays an essential role in hypertensive heart diseases, the mechanism remains elusive. Transgenic mice with cardiac overexpression of metallothionein, a heavy metal‐binding scavenger, were challenged with N G ‐nitro‐L‐arginine methyl ester (L‐NAME) for 14 days prior to measurement of myocardial contractile and intracellular Ca 2+ anomalies as well as cell signalling mechanisms using Western blot and immunofluorescence analysis. L‐NAME challenge elicited hypertension, macrophage infiltration, oxidative stress, inflammation and cardiac dysfunction manifested as increased proinflammatory macrophage marker F4/80, interleukin‐1β (IL‐1β), intracellular production, LV end systolic and diastolic diameters as well as depressed fractional shortening. L‐NAME treatment reduced mitochondrial membrane potential (MMP), impaired cardiomyocyte contractile and intracellular Ca 2+ properties as evidenced by suppressed peak shortening, maximal velocity of shortening/relengthening, rise in intracellular Ca 2+ , along with elevated baseline and peak intracellular Ca 2+ . These unfavourable mechanical changes and decreased MMP (except blood pressure and macrophage infiltration) were alleviated by overexpression of metallothionein. Furthermore, the apoptosis markers including BAD, Bax, Caspase 9, Caspase 12 and cleaved Caspase 3 were up‐regulated while the anti‐apoptotic marker Bcl‐2 was decreased by L‐NAME treatment. Metallothionein transgene reversed L‐NAME‐induced changes in Bax, Bcl‐2, BAD phosphorylation, Caspase 9, Caspase 12 and cleaved Caspase 3. Our results suggest that metallothionein protects against L‐NAME‐induced myocardial contractile anomalies in part through inhibition of apoptosis.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Cardiac‐specific overexpression of metallothionein attenuates L‐NAME‐induced myocardial contractile anomalies and apoptosis

Yang

Tan

et al. 2019

J Cellular Molecular Medi

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“…MT-2 has been shown to play a role in improving mitochondrial function in obesity and also in the prevention of diabetic nephropathy [36, 37]. Moreover, cardiac-specific overexpression of MT-2 has been shown to protect against myocardial dysfunction in a model of experimental hypertension [38]. These data further support our hypothesis that nanoSOD will be effective in ameliorating obesity-linked CVD.…”

Section: Discussionsupporting

confidence: 55%

Nanoformulated copper/zinc superoxide dismutase attenuates vascular cell activation and aortic inflammation in obesity

Saraswathi

Ganesan

Perriotte-Olson

et al. 2016

Biochemical and Biophysical Research Communications

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“…or partial mTOR deletion significantly reduced infarct size after ischemia through the restoration of autophagy [83]. Our previous studies also found that hypertension-induced mTOR activation altered cardiac morphology, function, and autophagy, which could be rescued by cardiac-specific overexpression of metallothionein [84, 85]. …”

Section: The Dual Role Of Mtor Signaling In Mi/r Injury Under Diabmentioning

confidence: 99%

Insights for Oxidative Stress and mTOR Signaling in Myocardial Ischemia/Reperfusion Injury under Diabetes

Zhao

Yang

2017

Oxidative Medicine and Cellular Longevity

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Diabetes mellitus (DM) displays a high morbidity. The diabetic heart is susceptible to myocardial ischemia/reperfusion (MI/R) injury. Impaired activation of prosurvival pathways, endoplasmic reticulum (ER) stress, increased basal oxidative state, and decreased antioxidant defense and autophagy may render diabetic hearts more vulnerable to MI/R injury. Oxidative stress and mTOR signaling crucially regulate cardiometabolism, affecting MI/R injury under diabetes. Producing reactive oxygen species (ROS) and reactive nitrogen species (RNS), uncoupling nitric oxide synthase (NOS), and disturbing the mitochondrial quality control may be three major mechanisms of oxidative stress. mTOR signaling presents both cardioprotective and cardiotoxic effects on the diabetic heart, which interplays with oxidative stress directly or indirectly. Antihyperglycemic agent metformin and newly found free radicals scavengers, Sirt1 and CTRP9, may serve as promising pharmacological therapeutic targets. In this review, we will focus on the role of oxidative stress and mTOR signaling in the pathophysiology of MI/R injury in diabetes and discuss potential mechanisms and their interactions in an effort to provide some evidence for cardiometabolic targeted therapies for ischemic heart disease (IHD).

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Cardiac-specific overexpression of metallothionein attenuates myocardial remodeling and contractile dysfunction in l-NAME-induced experimental hypertension: Role of autophagy regulation

Cited by 31 publications

References 70 publications

Cardiac‐specific overexpression of metallothionein attenuates L‐NAME‐induced myocardial contractile anomalies and apoptosis

Cardiac‐specific overexpression of metallothionein attenuates L‐NAME‐induced myocardial contractile anomalies and apoptosis

Nanoformulated copper/zinc superoxide dismutase attenuates vascular cell activation and aortic inflammation in obesity

Insights for Oxidative Stress and mTOR Signaling in Myocardial Ischemia/Reperfusion Injury under Diabetes

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