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.
Highlights
Intracellular calcium and cardiomyocyte contractility act in a well-concerted manner, known as excitation and contraction coupling [1]
We observed a significantly slower Ca2+ influx in cardiomyocytes overexpressing miR-132 but not in the miR212 overexpressing cells (Figures 1A,C). These results indicate that both miR-132 and miR-212 may regulate calcium reuptake, thereby explaining the prolongation of calcium kinetics
Knockdown of Ryr2 and VDAC2 did not display such mimicry (Figures 3A,B). These results suggest that SERCA2a and PTEN might be the targets of miR-132/212 involved in calcium handling in RNCM
Summary
Intracellular calcium and cardiomyocyte contractility act in a well-concerted manner, known as excitation and contraction coupling [1]. In a normal heart contraction-relaxation cycle, the cardiac action potential triggers calcium entry into the cell via Ltype calcium channels. This small increase of cytosolic calcium stimulates a bulk release of calcium from the sarcoplasmic reticulum (SR) into the cytosol via the Ryanodine receptor (RYR2) [1]. Cardiomyocytes cannot maintain a proper excitation and contraction coupling, which is still not fully understood but often associated with a decreased SERCA2a expression, which results in impaired re-uptake of Ca2+ into the SR [3, 4]. The results from the Phase 2b CUPID2 trial failed to show any significant treatment effect, probably related to ineffective normalization of SERCA2 levels under the conditions tested. To develop an effective pharmaceutical treatment to restore SERCA2 expression level, understanding the underlying mechanism of the down-regulation of SERCA2 in failing hearts is still warranted
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