The Aging Heart and Post-Infarction Left Ventricular Remodeling

Shih, Henry; Lee, Brian; Lee, Randall J.; Boyle, Andrew

doi:10.1016/j.jacc.2010.08.623

Cited by 174 publications

(130 citation statements)

References 81 publications

(85 reference statements)

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“…14,15 The activation of autophagy during stress conditions, such as myocardial ischemia and pressure overload, is generally an adaptive response to compensate for energy loss and to remove damaged mitochondria and protein aggregates. 16 However, exaggerated autophagic activity can result in the excessive degradation of organelles and, eventually, cell death. 15 The suppression of autophagy through the downregulation of Beclin-1 protects the heart from myocardial injuries due to ischemia reperfusion.…”

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confidence: 99%

MicroRNA-221 inhibits autophagy and promotes heart failure by modulating the p27/CDK2/mTOR axis

et al. 2014

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MicroRNAs have emerged as crucial regulators of cardiac homeostasis and remodeling in various cardiovascular diseases. We previously demonstrated that miR-221 regulated cardiac hypertrophy in vitro. In the present study, we demonstrated that the cardiac-specific overexpression of miR-221 in mice evoked cardiac dysfunction and heart failure. The lipidated form of microtubule-associated protein 1 light chain 3 was significantly decreased and sequestosome 1 was accumulated in cardiac tissues of transgenic (TG) mice, indicating that autophagy was impaired. Overexpression of miR-221 in vitro reduced autophagic flux through inhibiting autophagic vesicle formation. Furthermore, mammalian target of rapamycin (mTOR) was activated by miR-221, both in vivo and in vitro. The inactivation of mTOR abolished the miR-221-induced inhibition of autophagy and cardiac remodeling. Our previous study has demonstrated that cyclin-dependent kinase (CDK) inhibitor p27 was a direct target of miR-221 in cardiomyocytes. Consistently, the expression of p27 was markedly suppressed in the myocardia of TG mice. Knockdown of p27 by siRNAs was sufficient to mimic the effects of miR-221 overexpression on mTOR activation and autophagy inhibition, whereas overexpression of p27 rescued miR-221-induced autophagic flux impairment. Inhibition of CDK2 restored the impaired autophagic flux and rescued the cardiac remodeling induced by either p27 knockdown or miR-221 overexpression. These findings reveal that miR-221 is an important regulator of autophagy balance and cardiac remodeling by modulating the p27/CDK2/mTOR axis, and implicate miR-221 as a therapeutic target in heart failure. Cell Death and Differentiation ( Heart failure is the ultimate outcome of various cardiovascular diseases and is a leading cause of morbidity and mortality worldwide. Although drugs and other therapies have been developed for the management of heart failure, its 5-year mortality rate remains high.1 In response to myocardial stresses, the heart initially compensates with cardiomyocyte hypertrophy. Under prolonged stress, the heart undergoes irreversible cardiac remodeling, which finally results in cardiac decompensation and subsequent heart failure. The process of pathological cardiac remodeling involves the dysregulation of many coding and non-coding genes; however, not all of these genes have been well characterized.MicroRNAs (miRNAs) are endogenous small non-coding RNA molecules that posttranscriptionally regulate the degradation and/or translation of their target genes.2 A large body of evidence indicates that miRNA-mediated gene regulation has important roles in the control of cardiac homeostasis and pathological remodeling.3-8 We previously found that miR-221 is significantly upregulated in patients with hypertrophic cardiomyopathy (HCM) and in a mouse model of cardiac hypertrophy and heart failure induced by pressure overload. The in vitro overexpression of miR-221 alone is sufficient to increase the size of cardiomyocytes, accompanied by enhanced expression levels of...

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confidence: 99%

MicroRNA-221 inhibits autophagy and promotes heart failure by modulating the p27/CDK2/mTOR axis

et al. 2014

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“…Our study indicates that aging aggravates I/R injury. Additionally, aging increased myocardial apoptosis and depressed post-ischemic cardiac functional recovery (Jacob et al 2010a;Shih et al 2011). Meanwhile, aging also increased in vivo ROS.…”

Section: Discussionmentioning

confidence: 99%

Aging might augment reactive oxygen species (ROS) formation and affect reactive nitrogen species (RNS) level after myocardial ischemia/reperfusion in both humans and rats

Fan

Chen

Fang

et al. 2012

AGE

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Previous studies indicate aging results in significantly decreased cardiac function and increased myocardial apoptosis after myocardial ischemia/reperfusion (MI/R) in humans or rats. The underlying mechanisms of aging-exacerbated effects remain unknown. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are known to play vital roles in aging-related MI/R injury. Heretofore, the effects of aging upon ROS and RNS formation were not investigated in humans, which is the focus of the current study. Due to experimental limitations with clinical trials, an additional animal experiment was performed. All enrolled acute myocardial infarction (AMI) patients received percutaneous coronary intervention (PCI) therapy. AMI patients were assigned into two groups: adult (age <65, n034) and elderly (age ≥65, n045) AMI patients. Blood samples were obtained from all study participants at 24 h and 3 days post-PCI. Plasma/white blood cell (WBC) ROS and RNS markers (malondialdehyde (MDA), myeloperoxidase (MPO), reduced glutathione (GSH), inducible nitric oxide synthase (iNOS) activity, NOx, and nitrotyrosine) were determined. The same markers were determined in rat cardiac tissue after 24 h MI/R. Compared to the adult group, elderly patients manifested increased plasma MDA and MPO and decreased plasma GSH concentrations. No significant differences in plasma NOx or nitrotyrosine concentration existed between adult and elderly patients. Furthermore, WBC iNOS activity in elderly patients was significantly decreased compared to the adult group. The measurement of ROS markers in the rat experiments was consistent and supported human study data. Surprisingly, RNS markers (NOx and nitrotyrosine) in blood and heart tissue increased from young to middle-aged rats but decreased from middle age to old age. Aging augments ROS, which might exacerbate MI/R injury. Additionally, our data

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“…Previous studies have shown also that advanced age is a major risk factor for heart failure development (Shih et al 2011;Curtis et al 2008). Additionally, numerous reports have demonstrated that apoptosis plays a vital role in MI/R and post-ischemic heart failure pathogenesis (Narula et al 1996;Das 2007;Hikoso et al 2007;Dai and Rabinovitch 2009).…”

Section: Discussionmentioning

confidence: 99%

“…Although several animal studies have demonstrated significantly more apoptosis prevalent in the aged heart (Shih et al 2011;Dai and Rabinovitch 2009), two questions remain unanswered. Firstly, what is the effect of aging upon ischemia-induced apoptosis?…”

Section: Introductionmentioning

confidence: 99%

Aging might increase myocardial ischemia / reperfusion-induced apoptosis in humans and rats

Liu

Zhang

Chen

et al. 2011

AGE

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Previous studies indicated aging results in the significant cardiac function decreasing and myocardial apoptosis increasing in normal humans or rats. Additionally, animal experiments demonstrated aging increased myocardial ischemia / reperfusion (MI/R)-induced apoptosis. However, whether more myocardial apoptosis happen in the old acute myocardial infarction (AMI) patients is unclear. Reperfusion injury-induced apoptosis is an important cause of heart failure. This study determined the effect of aging upon myocardial apoptosis and cardiac function in patients suffering AMI. All enrolled AMI patients received percutaneous coronary intervention therapy. Volunteers and AMI patients were assigned to four groups: adult (age <65, n=24) volunteers, elderly (age ≥65, n=21) volunteers, adult (age <65, n=29) AMI patients, and elderly (age ≥65, n=36) AMI patients. Blood samples were obtained from all study participants. Plasma apoptotic markers (soluble form of Fas, tumor necrosis factor alpha, and interleukin 6) levels were determined. Cardiac function was evaluated with echocardiogram and Killip class. Due to lack of a direct apoptotic assay method in live human subjects, an additional animal experiment was performed. Both young (2 months) and old (24 months) rats were subjected to 30-min myocardial ischemia and 3 (for TUNEL/caspase activity apoptotic assay) or 24-h (for cardiac function determination) reperfusion. Compared to adult patients, the elderly patients manifested decreased cardiac function and increased plasma apoptotic marker levels significantly. The animal experiment results (cardiac function and plasma apoptotic markers assays) were consistent with the human result data. Animal TUNEL staining and caspase activity measurement revealed a higher myocardial apoptotic ratio in the older rat group. Aging exacerbated MI/R injury in humans and rats. Differential myocardial apoptosis may play a vital role in mediating the observed effects.

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The Aging Heart and Post-Infarction Left Ventricular Remodeling

Cited by 174 publications

References 81 publications

MicroRNA-221 inhibits autophagy and promotes heart failure by modulating the p27/CDK2/mTOR axis

MicroRNA-221 inhibits autophagy and promotes heart failure by modulating the p27/CDK2/mTOR axis

Aging might augment reactive oxygen species (ROS) formation and affect reactive nitrogen species (RNS) level after myocardial ischemia/reperfusion in both humans and rats

Aging might increase myocardial ischemia / reperfusion-induced apoptosis in humans and rats

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