Tanshinone IIA protects against sudden cardiac death induced by lethal arrhythmias via repression of microRNA‐1

Abstract

Background and purpose: 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. Experimental approach: 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 (IK1) 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. Key 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 IK1 current density and Kir2.1 protein after MI in rat ventricular myocytes, while quinidine further inhibited IK1/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 and implications: 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.

Lycium barbarum polysaccharides restore adverse structural remodelling and cardiac contractile dysfunction induced by overexpression of microRNA‐1

“…Undoubtedly all these data supported that the structural and functional protection of LBPs on Tg mouse hearts was due largely to the down‐regulation of miR‐1 level and subsequent restoration of target proteins essential for cardiac contractile function. Other studies found that tanshinone IIA, an active component of a traditional Chinese medicine based on Salvia Miltiorrhiza, protected against arrhythmogenesis after myocardial infarction and cardiac sudden death induced by lethal arrhythmias via repression of miR‐1,8, 13 and Propranolol exerted ischaemic cardioprotection related to down‐regulation of miR‐1,7 providing powerful supports for our cardioprotective result of LBPs on HF by down‐regulation of miR‐1. These findings not only help us understand the mechanisms underlying the beneficial effects of LBPs on HF, but also conceptually advance our view regarding miRNAs to serve as potential therapeutic drug targets.…”

“…Increasing lines of evidence have been rapidly evolving for the crucial roles of miRNAs in regulating diverse aspects of cardiac function and progression of HF 4, 5. And notably microRNA‐1 (miR‐1), a cardiac‐enriched miRNA, is in most close relation to heart conditions, and the changes in its expression have been discovered in a variety of heart diseases 6, 7, 8, 9, 10. Our previous report revealed that outcomes of miR‐1 overexpression induced adverse structural remodelling, which impaired cardiac contractile and diastolic function and even caused HF 11.…”

MicroRNA-1 aggravates cardiac oxidative stress by post-transcriptional modification of the antioxidant network

“…Deep sequencing of miRNAs from heart tissue has revealed that the abundance of miR-1 accounts for 40 % of all miRNAs. MiR-1 is involved in cardiac development and apoptosis and is elevated in the hearts of individuals with coronary artery diseases, ischemic arrhythmias, and heart failure (Ai et al 2010;Shan et al 2009;Lu et al 2009;Anderson and Mohler 2007;Yang et al 2007). Several studies have shown that miR-1 plays an important role in the regulation of cardiomyocyte apoptosis through post-transcriptional repression of signal proteins, such as Bcl-2 and IGF-1 (Tang et al 2009;Yu et al 2008).…”

The Role of Casein Kinase 2 in Ion Channel Remodeling After Myocardial Infarction

“…For example, upregulation of microRNA-1 (miR-1) and consequent reduction of Kir2.1 is observed in rat ventricular myocytes in a rodent model of MI. This is due to the increase in serum response factor (SFR), a transcriptional activator of the miR-1 gene [8].…”

“…For example, upregulation of microRNA-1 (miR-1) and consequent reduction of Kir2.1 is observed in rat ventricular myocytes in a rodent model of MI. This is due to the increase in serum response factor (SFR), a transcriptional activator of the miR-1 gene [8].In the current issue of Cardiovascular Drugs and Therapy, Li et al report evidence for kinase-dependent modulation of IK1 in an MI rodent model [9]. This work not only identifies a new potential target to attenuate the risk of heart failure after MI, but also provides additional information on the mechanisms of how valsartan, an angiotensin II type I receptor blocker attenuates the effect of MI.…”