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Published on: June 15, 2018
Spironolactone Regulates HCN Protein Expression Through Micro-RNA-1 in Rats With Myocardial Infarction
Hua-Dong Yu1, Shuang Xia, Cheng-Qin Zha
1*Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China; †Department of Cardiology, Longchang People's Hospital, Sichuan, China; and ‡Department of Cardiology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangdong, China.
Insights
Spironolactone, an aldosterone blocker, reduces ventricular arrhythmias after myocardial infarction (MI) by increasing miRNA-1. This upregulation downregulates hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, potentially explaining its protective effects.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Pharmacology
Background:
- Aldosterone blockers are known to reduce ventricular arrhythmias post-myocardial infarction (MI).
- The underlying molecular mechanisms for this protective effect remain largely unknown.
- Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are implicated in cardiac electrical activity and arrhythmias.
Purpose of the Study:
- To investigate the mechanism by which spironolactone affects hyperpolarization-activated cyclic nucleotide-gated (HCN) channel protein expression in ischemic rat myocardium following MI.
- To determine the role of miRNA-1 in mediating the effects of spironolactone on HCN channels.
Main Methods:
- Myocardial infarction (MI) was induced in rats.
- Rats were treated with spironolactone or vehicle, with some receiving antagomir-1 to suppress miRNA-1.
- HCN2, HCN4 protein and mRNA levels, and miRNA-1 levels were measured in myocardial tissue.
Main Results:
- Spironolactone significantly increased miRNA-1 levels in ischemic myocardium.
- Spironolactone downregulated both HCN2 and HCN4 protein and mRNA levels.
- Suppression of miRNA-1 using antagomir-1 led to increased HCN2 and HCN4 protein levels, but not mRNA levels.
Conclusions:
- Spironolactone increases miRNA-1 expression in the ischemic myocardium post-MI.
- Upregulation of miRNA-1 partially contributes to the posttranscriptional repression of HCN protein expression.
- This miRNA-1-mediated mechanism may underlie the reduction in MI-associated ventricular arrhythmias by spironolactone.
Abstract:
Emerging evidence has shown that aldosterone blockers reduced the incidence of ventricular arrhythmias in patients with myocardial infarction (MI). However, the mechanism remains unknown. In this study, we investigated the mechanism by which spironolactone, a classic aldosterone blocker, regulates hyperpolarization-activated cyclic nucleotide-gated channel (HCN) protein expression in ischemic rat myocardium after MI. Eighteen rats surviving 24 hours after MI were randomly assigned into 3 groups: MI, spironolactone, and spironolactone + antagomir-1. Six sham-operated rats had a suture loosely tied around the left coronary artery, without ligation. The border zone of the myocardial infarct was collected from each rat at 1 week after MI. HCN2 and HCN4 protein and messenger RNA (mRNA) level were measured in addition to miRNA-1 levels. Spironolactone significantly increased miRNA-1 levels and downregulated HCN2 and HCN4 protein and mRNA levels. miRNA-1 suppression with antagomir-1 increased HCN2 and HCN4 protein levels; however, HCN2 and HCN4 mRNA levels were not affected. These results suggested that spironolactone could increase miRNA-1 expression in ischemic rat myocardium after MI and that the upregulation of miRNA-1 expression partially contributed to the posttranscriptional repression of HCN protein expression, which may contribute to the effect of spironolactone to reduce the incidence of MI-associated ventricular arrhythmias.
