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...

ACE2 appears to counterbalance the vasopressor effect of angiotensin I converting enzyme (ACE) in the reninangiotensin system. We hypothesized that ACE2 polymorphisms could confer a high risk of hypertension and have an impact on the antihypertensive response to ACE inhibitors. The hypothesis was tested in two casecontrol studies and a clinical trial of 3,408 untreated hypertensive patients randomized to Atenolol, Hydrochlorothiazide, Captopril, or Nifedipine treatments for 4 weeks. ACE2 rs2106809 T allele was found to confer a 1.6-fold risk for hypertension in women (95% confidence interval (CI), 1.132.06), whereas when combined with the effect of the ACE DD genotype, the risk was 2.34-fold (95% CI, 1.754.85) in two independent samples. The adjusted diastolic blood pressure response to Captopril was 3.3 mm Hg lower in ACE2 T allele carriers than in CC genotype carriers (P=0.019) in women. We conclude that the ACE2 T allele confers a high risk for hypertension and reduced antihypertensive response to ACE inhibitors.

The major epigenetic features of mammalian cells include DNA methylation, posttranslational histone modifications and RNA-based mechanisms including those controlled by small non-coding RNAs (microRNAs (miRNAs)). An important aspect of epigenetic mechanisms is that they are potentially reversible and may be influenced by nutritional-environmental factors and through gene-environment interactions. Studies on epigenetic modulations could help us understand the mechanisms involved in essential hypertension and further prevent it's progress. This review is focused on new knowledge on the role of epigenetics, from DNA methylation to miRNAs, in essential hypertension.

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