miR-132/212 Impairs Cardiomyocytes Contractility in the Failing Heart by Suppressing SERCA2a

Abstract

Compromised cardiac function is a hallmark for heart failure, mostly appearing as decreased contractile capacity due to dysregulated calcium handling. Unfortunately, the underlying mechanism causing impaired calcium handling is still not fully understood. Previously the miR-132/212 family was identified as a regulator of cardiac function in the failing mouse heart, and pharmaceutically inhibition of miR-132 is beneficial for heart failure. In this study, we further investigated the molecular mechanisms of miR-132/212 in modulating cardiomyocyte contractility in the context of the pathological progression of heart failure. We found that upregulated miR-132/212 expressions in all examined hypertrophic heart failure mice models. The overexpression of miR-132/212 prolongs calcium decay in isolated neonatal rat cardiomyocytes, whereas cardiomyocytes isolated from miR-132/212 KO mice display enhanced contractility in comparison to wild type controls. In response to chronic pressure-overload, miR-132/212 KO mice exhibited a blunted deterioration of cardiac function. Using a combination of biochemical approaches and in vitro assays, we confirmed that miR-132/212 regulates SERCA2a by targeting the 3′-end untranslated region of SERCA2a. Additionally, we also confirmed PTEN as a direct target of miR-132/212 and potentially participates in the cardiac response to miR132/212. In end-stage heart failure patients, miR-132/212 is upregulated and correlates with reduced SERCA2a expression. The up-regulation of miR-132/212 in heart failure impairs cardiac contractile function by targeting SERCA2a, suggesting that pharmaceutical inhibition of miR-132/212 might be a promising therapeutic approach to promote cardiac function in heart failure patients.

Transient Post-Natal Exposure to Xenoestrogens Induces Long-Term Alterations in Cardiac Calcium Signaling

“…Indeed, in the developmental origins of health and disease, epigenetics is described as a key player [ 29 ]. Interestingly, studies reported DNA methylation [ 30 ] and microRNAs [ 31 , 32 ] as regulators of SERCA2. In our model, alteration of SERCA2 due to DNA methylation appeared less likely since no modification was observed in SERCA2 mRNA levels.…”

Advances in miR-132-Based Biomarker and Therapeutic Potential in the Cardiovascular System

“…Lei et al showed that miR-132/212 overexpression prolongs calcium decay in isolated neonatal rat cardiomyocytes, whereas cardiomyocytes isolated from miR-132/212 KO mice display enhanced contractility in comparison to wild type controls. The authors also found upregulation of miR-132/212 and reduced SERCA2 protein expression in end-stage heart failure patients of different etiologies, including dilated cardiomyopathy, hypertrophic cardiomyopathy, and ischemic cardiomyopathy ( Lei et al, 2021 ). Besides, it was also suggested that elevated miR-132/212 can lower SERCA2 activity indirectly via inhibition of PTEN, which is a direct target of miR-132/212 and loss of function in cardiomyocytes leading to a dramatic decrease in contractility ( Crackower et al, 2002 ; Ruan et al, 2009 ).…”

Editorial Research Topic: Non-coding RNA as Therapeutic Target: A Game Changer in Cardiac Regenerative Strategies?

“…These contradictory findings could be due to timing issues. Moreover, in a recent publication Lei et al ( 2021 ) show that in a mouse model of pressure overload miR-212/132 knockout leads to improved cardiac function in comparison to WT animals. Importantly, the underlying mechanisms seem to be conserved in mammals, as therapeutic targeting of the miR-212/132 family in mice and pigs showed promising results for the treatment of heart failure (Foinquinos et al, 2020 ; Batkai et al, 2021 ).…”