Tanshinone IIA protects against sudden cardiac death induced by lethal arrhythmias via repression of microRNA-1.
OBJECTIVE
Tanshinone IIA is an active component of a traditional Chinese medicine based on Salvia miltiorrhiza, which reduces sudden cardiac death by suppressing ischaemic arrhythmias. However, the mechanisms underlying the anti-arrhythmic effects remain unclear.


METHODS
A model of myocardial infarction (MI) in rats by ligating the left anterior descending coronary artery was used. Tanshinone IIA or quinidine was given daily, before (7 days) and after (3 months) MI; cardiac electrical activity was monitored by ECG recording. Whole-cell patch-clamp techniques were used to measure the inward rectifying K(+) current (I(K1)) in rat isolated ventricular myocytes. Kir2.1 and serum response factor (SRF) levels were analysed by Western blot and microRNA-1 (miR-1) level was determined by real-time RT-PCR.


RESULTS
Tanshinone IIA decreased the incidence of arrhythmias induced by acute cardiac ischaemia and mortality in rats 3 months after MI. Tanshinone IIA restored the diminished I(K1) current density and Kir2.1 protein after MI in rat ventricular myocytes, while quinidine further inhibited I(K1)/Kir2.1. MiR-1 was up-regulated in MI, possibly due to the concomitant increase in SRF, a transcriptional activator of the miR-1 gene, accounting for decreased Kir2.1. Treatment with tanshinone IIA prevented increased SRF and hence increased miR-1 post-MI, whereas quinidine did not.


CONCLUSIONS
Down-regulation of miR-1 and consequent recovery of Kir2.1 may account partially for the efficacy of tanshinone IIA in suppressing ischaemic arrhythmias and cardiac mortality. These finding support the proposal that miR-1 could be a potential therapeutic target for the prevention of ischaemic arrhythmias.
Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Harbin, Heilongjiang, China.
Hongli
H
Shan
Xuelian
X
Li
Zhenwei
Z
Pan
Li
L
Zhang
Benzhi
B
Cai
Yong
Y
Zhang
Chaoqian
C
Xu
Wenfeng
W
Chu
Guofen
G
Qiao
Baoxin
B
Li
Yanjie
Y
Lu
Baofeng
B
Yang
D045784:Abietanes; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D016757:Death, Sudden, Cardiac / Q000209:etiology / Q000517:prevention & control*; D015536:Down-Regulation; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D004562:Electrocardiography; D066298:In Vitro Techniques; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis*; D009203:Myocardial Infarction / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010616:Phenanthrenes / Q000494:pharmacology*; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors / Q000502:physiology; D011802:Quinidine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D026362:Serum Response Factor / Q000378:metabolism
D045784:Abietanes; D000889:Anti-Arrhythmia Agents; D004365:Drugs, Chinese Herbal; C489461:Kir2.1 channel; C542191:MIRN1 microRNA, rat; D035683:MicroRNAs; D010616:Phenanthrenes; D024661:Potassium Channels, Inwardly Rectifying; D026362:Serum Response Factor; C021751:tanshinone; D011802:Quinidine