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Emerging evidence reveals that autophagy plays crucial roles in cardiac hypertrophy. Long noncoding RNAs (lncRNAs) are novel transcripts that function as gene regulators. However, it is unclear whether lncRNAs regulate autophagy in cardiac hypertrophy. Here, we identified a novel transcript named lncRNA Gm15834, which was upregulated in the transverse aortic constriction (TAC) model in vivo and the angiotensin-II (Ang-II)-induced cardiac hypertrophy model in vitro and was regulated by nuclear factor kappa B (NF-κB). Importantly, forced expression of lncRNA Gm15834 enhanced autophagic activity of cardiomyocytes and promoted myocardial hypertrophy, whereas silencing of lncRNA Gm15834 attenuated autophagy-induced myocardial hypertrophy. Mechanistically, we found that lncRNA Gm15834 could function as an endogenous sponge RNA of microRNA (miR)-30b-3p, which was downregulated in cardiac hypertrophy. Inhibition of miR-30b-3p enhanced cardiomyocyte autophagic activity and aggravated myocardial hypertrophy, whereas overexpression of miR-30b-3p suppressed autophagy-induced myocardial hypertrophy by targeting the downstream autophagy factor of unc-51-like kinase 1 (ULK1). Moreover, inhibition of lncRNA Gm15834 by adeno-associated virus carrying short hairpin RNA (shRNA) suppressed cardiomyocyte autophagic activity, improved cardiac function, and mitigated cardiac hypertrophy. Taken together, our study identified a novel regulatory axis encompassing lncRNA Gm15834/miR-30b-3p/ULK1/autophagy in cardiac hypertrophy, which may provide a potential therapy target for cardiac hypertrophy.

Cardiac hypertrophy, a response of the heart to increased workload, is a major risk factor for heart failure. Myostatin (MSTN) is an inhibitor of myogenesis, regulating the number and size of skeletal myocytes. In recent years, cardiomyocyte autophagy also has been considered to be involved in controlling the hypertrophic response. However, less is known about the detailed mechanism of MSTN on cardiac hypertrophy via regulation of cardiomyocyte autophagy. In this study, we found that the deletion of MSTN potentiated abdominal aorta coarctation (AAC) and angiotensin II (Ang II)-induced pathological cardiac hypertrophy and cardiac autophagy; however, AAC and Ang II-induced cardiac hypertrophic phenotype and cardiac autophagy were dramatically diminished by MSTN in vivo and in vitro. Mechanistically, the anti-hypertrophic and anti-autophagic effects mediated by MSTN in response to pathological stimuli were associated with the direct inactivation of activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) and activation of the peroxisome proliferator-activated receptor gamma (PPARγ)/nuclear factor κB (NF-κB) signaling pathway. Additionally, miR-128 aggravated the progression of cardiac hypertrophy through suppressing its target PPARγ. Furthermore, MSTN downregulated miR-128 expression induced by AAC and Ang II. Taken together, MSTN significantly blunts pathological cardiac hypertrophy and dysfunction, at least in part, by inhibiting excessive cardiac autophagy via blocking AMPK/mTOR and miR-128/PPARγ/NF-κB signaling pathways.

The molecular characteristics of ferroptosis in cardiac hypertrophy have been rarely studied. Especially, there have been no studies to investigate the regulatory mechanisms of docosahexaenoic acid (DHA) on ferroptosis in cardiac hypertrophy. This study was designed to determine the role of ferroptosis in microvascular injury, and investigate the contribution of DHA in suppressing ferroptosis and preventing pressure overload-mediated endothelial damage. Our results indicated that the expression of interferon regulating factor 3 (IRF3) was primarily inhibited by pressure overload and consequently caused endothelial ferroptosis. Nevertheless, administration of DHA increased IRF3 expression and provided a pro-survival advantage for the endothelial system in the context of pressure overload. Experimental studies clearly showed that inhibition of IRF3 down-regulated SLC7A11 expression, and the latter leaded to the increase in the activities of arachidonate 12-lipoxygenase, which obligated cardiac microvascular endothelial cells to undergo ferroptosis via augmenting lipid peroxides. Interestingly, DHA supplementation suppressed endothelial ferroptosis via up-regulation of IRF3. Taken together, our studies identified the IRF3-SLC7A11-arachidonate 12-lipoxygenase axis as a new pathway responsible for pressure overload-mediated microvascular damage via initiating endothelial ferroptosis. In contrast, DHA treatment up-regulated the expression of IRF3 and thus reduced cellular ferroptosis, conferring a protective advantage to the endothelial system in pressure overload. These findings revealed that targeting IRF3 might be a useful therapeutic strategy for cardioprotection in cardiac hypertrophy and heart failure.

Acute myocardial infarction (AMI) is a type of cardiovascular diseases that severely threatens human being, but the mechanisms have not been thoroughly clarified. Here, we detected that microRNA-15a-5p (miR-15a-5p) was up-regulated in AMI. Knockdown of miR-15a-5p reduced cell mortality in hypoxic-treated myocardial cells. In addition, we determined that glutathione peroxidase4 (GPX4) was the direct target of miR-15a-5p by luciferase reporter assay. Over-expression of miR-15a-5p strengthened ferroptosis, then aggravated myocardial cell hypoxia injury. Mechanistically, silencing transcription factor early growth response-1 (Egr-1) inhibited the level of miR-15a-5p, increased the protein expression of GPX4, accompanied by reduced ferroptosis and alleviated myocardial injury. In summary, these results provide a novel signaling pathway during the progression of acute myocardial infarction, namely Egr-1/miR-15a-5p/GPX4/ferroptosis.

Background Cardiac hypertrophy is an adaptive response of the myocardium to pressure or volume overload. Recent evidences indicate that allicin can prevent cardiac hypertrophy. However, it is not clear whether allicin alleviates cardiac hypertrophy by inhibiting autophagy. Purpose We aimed to investigate the effects of allicin on pressure overload-induced cardiac hypertrophy, and further to clarify the related mechanism. Study design/methods Cardiac hypertrophy was successfully established by abdominal aortic constriction (AAC) in rats, and cardiomyocytes hypertrophy was simulated by angiotensin II (Ang II) in vitro. Hemodynamic parameters were monitored by organism function experiment system in vivo. The changes of cell surface area were observed using HE and immunofluorescence staining in vivoand in vitro, respectively. The expressions of cardiac hypertrophy relative protein (BNP and β-MHC), autophagy marker protein (LC3-II and Beclin-1), Akt, PI3K and ERK were detected by western blot. Results Allicin could improve cardiac function, and reduce cardiomyocytes size, and decrease BNP and β-MHC protein expressions. Further results showed that allicin could lower LC3-II and Beclin-1 protein expressions both in vivo and in vitro experiments. And pharmacological inhibitor of mTOR, rapamycin could antagonize the effects of allicin on Ang II-induced cardiac hypertrophy and autophagy. Simultaneously, allicin could promote the expressions of p-Akt, p-PI3K and p-ERK protein. Conclusion These findings reveal a novel mechanism of allicin attenuating cardiac hypertrophy which allicin could inhibit excessive autophagy via activating PI3K/Akt/mTOR and MAPK/ERK/mTOR signaling pathways.