title: Spironolactone Regulates HCN Protein Expression Through Micro-RNA-1 in Rats With Myocardial Infarction.
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.
authors.affiliation: *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.
authors.forename: Hua-Dong
authors.initials: HD
authors.lastname: Yu
authors.forename: Shuang
authors.initials: S
authors.lastname: Xia
authors.forename: Cheng-Qin
authors.initials: CQ
authors.lastname: Zha
authors.forename: Song-Bai
authors.initials: SB
authors.lastname: Deng
authors.forename: Jian-Lin
authors.initials: JL
authors.lastname: Du
authors.forename: Qiang
authors.initials: Q
authors.lastname: She
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D009841:Oligonucleotides / Q000235:genetics / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D013148:Spironolactone / Q000494:pharmacology*; D013997:Time Factors
chemical_list: C513836:HCN4 protein, rat; C578712:Hcn2 protein, rat; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; C542191:MIRN1 microRNA, rat; D035683:MicroRNAs; D000451:Mineralocorticoid Receptor Antagonists; D009841:Oligonucleotides; D015221:Potassium Channels; D012333:RNA, Messenger; D013148:Spironolactone