PDE5 inhibitor sildenafil attenuates cardiac microRNA 214 upregulation and pro-apoptotic signaling after chronic alcohol ingestion in mice

Abstract

Abusive chronic alcohol consumption can cause metabolic and functional derangements in the heart and is a risk factor for development of non-ischemic cardiomyopathy. microRNA 214 (miR-214) is a molecular sensor of stress signals that negatively impacts cell survival. Considering cardioprotective and microRNA modulatory effects of sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, we investigated the impact of chronic alcohol consumption on cardiac expression of miR-214 and its anti-apoptotic protein target, Bcl-2 and whether sildenafil attenuates such changes. Adult male FVB mice received unlimited access to either normal liquid diet (control), alcohol diet (35% daily calories intake), or alcohol + sildenafil (1 mg/kg/day, p.o.) for 14 weeks (n = 6–7/group). The alcohol-fed groups with or without sildenafil had increased total diet consumption and lower body weight as compared with controls. Echocardiography-assessed left ventricular function was unaltered by 14-week alcohol intake. Alcohol-fed group had 2.6-fold increase in miR-214 and significant decrease in Bcl-2 expression, along with enhanced phosphorylation of ERK1/2 and cleavage of PARP (marker of apoptotic DNA damage) in the heart. Co-ingestion with sildenafil blunted the alcohol-induced increase in miR-214, ERK1/2 phosphorylation, and maintained Bcl-2 and decreased PARP cleavage levels. In conclusion, chronic alcohol consumption triggers miR-214-mediated pro-apoptotic signaling in the heart, which was prevented by co-treatment with sildenafil. Thus, PDE5 inhibition may serve as a novel protective strategy against cardiac apoptosis due to chronic alcohol abuse.

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Funding

This study was supported in part by grants from the National Institutes of Health (CA221813, DK120866, HL118808 to RCK, and HL134366 to RCK & AD). LX is a recipient of Pauley Pilot Research Grant (Virginia Commonwealth University).

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AS, LX, and RCK designed the study; AS, LX, FNA, and AD performed the experiments and analyzed the data; AS, LX, and RCK wrote the manuscript; all authors substantially contributed to the interpretation of the data, critically revised the manuscript, and approved the final version.

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Correspondence to Rakesh C. Kukreja.

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Samidurai, A., Xi, L., Salloum, F.N. et al. PDE5 inhibitor sildenafil attenuates cardiac microRNA 214 upregulation and pro-apoptotic signaling after chronic alcohol ingestion in mice. Mol Cell Biochem 471, 189–201 (2020). https://doi.org/10.1007/s11010-020-03779-7

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Keywords

  • microRNA
  • Alcoholic cardiomyopathy
  • PDE5 inhibitor
  • Apoptosis