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Cardiac hypertrophy and consequent contractile dysfunction continue to burden Western society. Cardiomyocyte cyclic AMP (cAMP) and calcium are driving forces behind cardiomyocyte contraction. Distortion of their balance may induce HF, but specific therapies aiming at restoring physiological cAMP/calcium signaling are lacking.We recently identified microRNA-139 (miR-139) to be downregulated in failing human hearts. MiR-139 resides in the phosphodiesterase gene PDE2A and is predicted to target several phosphodiesterase messengers. In view of the central role of phosphodiesterases in controlling cardiac cAMP and calcium signaling, we hypothesized that miR-139 may affect HF progression by fine-tuning cAMP and calcium balances.Adeno-associated virus serotype 9 (AAV9), either empty control or expressing pre-miR-139, was administered to male C57Bl/6J mice. After allowing transgene expression for 3 weeks, mice were subjected to sham treatment or 4 weeks of pressure overload by subcutaneous Angiotensin II infusion (AngII, 2,5 mg/(kg·d). MiR-139 overexpression mildly aggravated HF development upon AngII with echocardiographically measured fractional shortening decreasing by 24±7% in AAV9-control AngII and by 46±5% in AAV9-pre-miR-139 AngII (n>11/group; p=0.14). In AAV9-control mice, AngII infusion led to concentric hypertrophy with an increased relative wall thickness (RWT) of 35±6%, whereas mice overexpressing miR-139 showed a rather eccentric form of hypertrophy with an increased RWT of 14±7% (p<0.05). The fraction of unphosphorylated cardiac troponin I (cTnI), a substrate of the cAMP dependent protein kinase A (PKA), tended to increase upon AngII infusion only in mice overexpressing miR-139 (n=4/group; p=0.11), indicating a reduced relaxation rate due to increased calcium sensitivity, a feature commonly observed in HF. Complimentary to these data, in vivo knockdown of mir-139 by cholesterol-tagged antagomiRs (20mg/kg) on three consecutive days before start of AngII infusion dampened the development of pressure overload-induced cardiac hypertrophy (increase in HW/TL: ctrl: 48±10%, n=4; antagomiR: 25±7%, n=7; p=0.16).In conclusion, cardiac downregulation of miR-139 upon pressure overload is a protective response to preserve cardiac function. AAV9-mediated overexpression of miR-139 promotes cardiac dilation and predisposes to HF. Upcoming experiments will aim at defining the molecular mechanism by which miR-139/phosphodiesterase signaling affects cardiac pathophysiology. [ABSTRACT FROM PUBLISHER]

Purpose: Despite major advances in the treatment of cardiovascular diseases, heart failure (HF) remains one of the top causes of death world-wide. The implications of microRNAs in this process are well accepted but still only incompletely understood. The microRNAs 221-3p and 222-3p are processed from a common precursor and share the same seed sequence and thus form the microRNA-221/222 family (miR-221/222). Both microRNAs were found to be involved in myoblast differentiation and are upregulated after aortic banding in mice. We therefore hypothesized that the miR-221/222 family is involved in the pathophysiology of cardiac hypertrophy and failure upon pressure overload.Methods and results: In a genome wide screen for microRNAs regulated in human dilated cardiomyopathy, we found miR-222 levels to be significantly decreased (p<0.01). MiR-221/222 were also downregulated in neonatal rat cardiomyocytes (nRCMs) upon stimulation with the pro-hypertrophic compound phenylephrine (PE) (p<0.05). Interestingly, the overexpression of these miRs in nRCMs using mimics significantly blunted the induction of the hypertrophy markers Bnp and skeletal alpha actin (Acta1) in nRCMs upon stimulation with PE.To investigate the role of miR-221/222 in pressure overload-induced heart failure, we simultaneously injected anti-miR-221 and anti-miR-222 antisense oligonucleotides (ASOs) or scrambled control oligonucleotides (SCOs) in male C57BL/6 mice 3 days before implanting angiotensin II-filled osmotic minipumps (AngII, 2.5 mg/(kg d)). After 4 weeks, we assessed cardiac function and histology as well as molecular changes in the left ventricle. Surprisingly, we did not find an effect of miR-221/222 inhibition on overall cardiac hypertrophy after AngII infusion (HW/TL: 8.04 vs 7.92 mg/mm, p>0.05). However, interstitial fibrosis was significantly increased upon AngII stimulation in mice that received miR-221/222 ASOs as compared to SCOs (6.1 vs 3.7% LV area, p<0.05). On the mRNA level, these mice also showed a 2.9-fold higher induction of Anp upon AngII stimulation (p~0.10), in line with anti-hypertrophic effects of miR-221/222 mimics shown in vitro.Conclusions: Taken together, our results indicate a protective effect of the microRNA-221/222 family in the stressed heart. Inhibition of miR-221/222 prior to pressure overload in mice led to increased fibrosis indicating adverse remodeling. In vitro, a direct effect of miR-221/222 overexpression on the hypertrophic response of nRCMs could be shown. Further experiments will aim at identifying the function of the miR-221/222 family both in cardiac fibroblast and cardiomyocytes. [ABSTRACT FROM PUBLISHER]

Half of all heart failure patients have preserved ejection fraction (HFpEF). Comorbidities associated with and contributing to HFpEF include obesity, diabetes and hypertension. Still, the underlying pathophysiological mechanisms of HFpEF are unknown. A preliminary consensus proposes that the multi-morbidity triggers a state of systemic, chronic low-grade inflammation, and microvascular dysfunction, causing reduced nitric oxide bioavailability to adjacent cardiomyocytes. As a result, the cardiomyocyte remodels its contractile elements and fails to relax properly, causing diastolic dysfunction, and eventually HFpEF. HFpEF is a complex syndrome for which currently no efficient therapies exist. This is notably due to the current one-size-fits-all therapy approach that ignores individual patient differences. MicroRNAs have been studied in relation to pathophysiological mechanisms and comorbidities underlying and contributing to HFpEF. As regulators of gene expression, microRNAs may contribute to the pathophysiology of HFpEF. In addition, secreted circulating microRNAs are potential biomarkers and as such, they could help stratify the HFpEF population and open new ways for individualized therapies. In this review, we provide an overview of the ever-expanding world of non-coding RNAs and their contribution to the molecular mechanisms underlying HFpEF. We propose prospects for microRNAs in stratifying the HFpEF population. MicroRNAs add a new level of complexity to the regulatory network controlling cardiac function and hence the understanding of gene regulation becomes a fundamental piece in solving the HFpEF puzzle.

Aims: The overloaded heart remodels by cardiomyocyte hypertrophy and interstitial fibrosis, which contributes to the development of heart failure. Signalling via the TGFβ-pathway is crucial for this remodelling. Here we tested the hypothesis that microRNAs in the overloaded heart regulate this remodelling process via inhibition of the TGFβ-pathway., Methods and Results: We show that the miRNA-15 family, which we found to be up-regulated in the overloaded heart in multiple species, inhibits the TGFβ-pathway by targeting of TGFBR1 and several other genes within this pathway directly or indirectly, including p38, SMAD3, SMAD7, and endoglin. Inhibition of miR-15b by subcutaneous injections of LNA-based antimiRs in C57BL/6 mice subjected to transverse aorta constriction aggravated fibrosis and to a lesser extent also hypertrophy., Conclusion: We identified the miR-15 family as a novel regulator of cardiac hypertrophy and fibrosis acting by inhibition of the TGFβ-pathway., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

With a progressively growing elderly population, ageing-associated pathologies such as cardiovascular diseases are becoming an increasing economic, social, and personal burden for Western societies. Interestingly, all ageing-associated diseases share a common denominator: inflammation. Recently, microRNAs were shown to be implicated in the full range of processes of ageing, inflammation, and cardiovascular diseases. This review focuses on their role in cardiovascular diseases with emphasis on their implication in the inflammatory processes that accompany heart failure, atherosclerosis, coronary artery disease, and finally obesity and diabetes as components of the ageing-associated metabolic syndrome.