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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 (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. 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 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 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.

SUBMITTER: Shan H

PROVIDER: S-EPMC2782332 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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

Shan Hongli H Li Xuelian X Pan Zhenwei Z Zhang Li L Cai Benzhi B Zhang Yong Y Xu Chaoqian C Chu Wenfeng W Qiao Guofen G Li Baoxin B Lu Yanjie Y Yang Baofeng B

British journal of pharmacology 20090923 5

<h4>Background and purpose</h4>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.<h4>Experimental approach</h4>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 ...[more]

PMID: 19775284

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Project description:Lethal ventricular arrhythmia‑sudden cardiac death (LVA‑SCD) occurs frequently during the early stage of myocardial ischemia (MI). However, the mechanism underlying higher LVA‑SCD incidence is still poorly understood. The present study aimed to explore the role of mitochondrial reactive oxygen species (mROS) and Ca2+ crosstalk in promoting LVA‑SCD in early MI. RyR2 S2814A mice and their wild‑type littermates were used. MitoTEMPO was applied to scavenge mitochondrial ROS (mROS). Mice were subjected to severe MI and the occurrence of LVA‑SCD was evaluated. Levels of mitochondrial ROS and calcium (mitoCa2+), cytosolic ROS (cytoROS), and calcium (cytoCa2+), RyR2 Ser‑2814 phosphorylation, CaMKII Met‑282 oxidation, mitochondrial membrane potential (MMP), and glutathione/oxidized glutathione (GSH/GSSG) ratio in the myocardia were detected. Dynamic changes in mROS after hypoxia were investigated using H9c2 cells. Moreover, the myocardial phosphoproteome was analyzed to explore the related mechanisms facilitating mROS‑Ca2+ crosstalk and LVA‑SCD. There was a high incidence (~33.9%) of LVA‑SCD in early MI. Mice who underwent SCD displayed notably elevated levels of myocardial ROS and mROS, and the latter was validated in H9c2 cells. These mice also demonstrated overloads of cytoplasmic and mitochondrial Ca2+, decreased MMP and reduced GSH/GSSG ratio, upregulated RyR2‑S2814 phosphorylation and CaMKII‑M282 oxidation and transient hyperphosphorylation of mitochondrial proteomes in the myocardium. mROS‑specific scavenging by a mitochondria‑targeted antioxidant agent (MitoTEMPO) corrected these SCD‑induced alterations. S2814A mice with a genetically inactivated CaMKII phosphorylation site in RyR2 exhibited decreased overloads in cytoplasmic and mitochondrial Ca2+ and demonstrated similar effects as MitoTEMPO to correct SCD‑induced changes and prevent SCD post‑MI. The data confirmed crosstalk between mROS and Ca2+ in promoting LVA‑SCD. Therefore, we provided evidence that there is a higher incidence of LVA‑SCD in early MI, which may be attributed to a positive feedback loop between mROS and Ca2+ imbalance.

Project description:AimsThe aim of this study was to examine the effect of dapagliflozin on the incidence of ventricular arrhythmias and sudden death in patients with heart failure and reduced ejection fraction (HFrEF).Methods and resultsIn a post hoc analysis of DAPA-HF, we examined serious adverse event reports related to ventricular arrhythmias or cardiac arrest, in addition to adjudicated sudden death. The effect of dapagliflozin, compared with placebo, on the composite of the first occurrence of any serious ventricular arrhythmia, resuscitated cardiac arrest, or sudden death was examined using Cox proportional hazards models. A serious ventricular arrhythmia was reported in 115 (2.4%) of the 4744 patients in DAPA-HF (ventricular fibrillation in 15 patients, ventricular tachycardia in 86, 'other' ventricular arrhythmia/tachyarrhythmia in 12, and torsade de pointes in 2 patients). A total of 206 (41%) of the 500 cardiovascular deaths occurred suddenly. Eight patients survived resuscitation from cardiac arrest. Independent predictors of the composite outcome (first occurrence of any serious ventricular arrhythmia, resuscitated cardiac arrest or sudden death), ranked by chi-square value, were log-transformed N-terminal pro-B-type natriuretic peptide, history of ventricular arrhythmia, left ventricular ejection fraction, systolic blood pressure, history of myocardial infarction, male sex, body mass index, serum sodium concentration, non-white race, treatment with dapagliflozin, and cardiac resynchronization therapy. Of participants assigned to dapagliflozin, 140/2373 patients (5.9%) experienced the composite outcome compared with 175/2371 patients (7.4%) in the placebo group [hazard ratio 0.79 (95% confidence interval 0.63-0.99), P = 0.037], and the effect was consistent across each of the components of the composite outcome.ConclusionsDapagliflozin reduced the risk of any serious ventricular arrhythmia, cardiac arrest, or sudden death when added to conventional therapy in patients with HFrEF.Clinical trial registrationClinicalTrials.gov unique identifier: NCT03036124 (DAPA-HF).

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

Publications

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

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