The mechanical effects of CRT promoting autophagy via mitochondrial calcium uniporter down‐regulation and mitochondrial dynamics alteration

Abstract

The mechanism of cardiac resynchronization therapy ( CRT ) remains unclear. In this study, mitochondria calcium uniporter ( MCU ), dynamin‐related protein‐1 ( DNM 1L/Drp1) and their relationship with autophagy in heart failure ( HF ) and CRT are investigated. Thirteen male beagle's dogs were divided into three groups (sham, HF , CRT ). Animals received left bundle branch ( LBB ) ablation followed by either 8‐week rapid atrial pacing or 4‐week rapid atrial pacing and 4‐week biventricular pacing. Cardiac function was evaluated by echocardiography. Differentially expressed genes ( DEG s) were detected by microarray analysis. General morphological changes, mitochondrial ultrastructure, autophagosomes and mitophagosomes were investigated. The cardiomyocyte stretching was adopted to imitate the mechanical effect of CRT . Cells were divided into three groups (control, angiotensin‐ II and angiotensin‐ II + stretching). MCU , DNM 1L/Drp1 and autophagy markers were detected by western blots or immunofluorescence. In the present study, CRT could correct cardiac dysfunction, decrease cardiomyocyte's size, alleviate cardiac fibrosis, promote the formation of autophagosome and mitigate mitochondrial injury. CRT significantly influenced gene expression profile, especially down‐regulating MCU and up‐regulating DNM 1L/Drp1. Cell stretching reversed the angiotensin‐ II induced changes of MCU and DNM 1L/Drp1 and partly restored autophagy. CRT 's mechanical effects down‐regulated MCU , up‐regulated DNM 1L/Drp1 and subsequently enhanced autophagy. Besides, the mechanical stretching prevented the angiotensin‐ II ‐induced cellular enlargement.

Longevity genes, cardiac ageing, and the pathogenesis of cardiomyopathy: implications for understanding the effects of current and future treatments for heart failure

“… 177–180 The effect of cardiac resynchronization to effect reverse remodelling is accompanied by activation of autophagic flux and improvement in mitochondrial function. 181 Therefore, currently available treatments for heart failure appear to exert a consistently favourable influence on the interplay of SIRT1/AMPK and Akt/mTOR in a manner that promotes autophagy.…”

Advances in the mechanism and treatment of mitochondrial quality control involved in myocardial infarction

“…PINK/Parkin can mediate mitophagy during MI. It has been found that cardiac resynchronization therapy following heart failure caused by MI and berberine, which belongs to the traditional Chinese medicine, can all induce an increase in PINK/Parkin expression and mitophagy 107,108 . Yao et al 80 found that an injection of hydrogen‐rich saline can attenuate inflammation and apoptosis of the damaged myocardium by enhancing mitophagy.…”

“…It has been found that cardiac resynchronization therapy following heart failure caused by MI and berberine, which belongs to the traditional Chinese medicine, can all induce an increase in PINK/Parkin expression and mitophagy. 107,108 Yao et al 80 found that an injection of hydrogen-rich saline can attenuate inflammation and apoptosis of the damaged myocardium by enhancing mitophagy. The authors further found that after knocking out the PINK gene, the protective effect of hydrogen was partially reversed, suggesting that hydrogen can enhance PINK/Parkin-mediated mitophagy to attenuate MI.…”

Mitochondrial Calcium Uniporter Structure and Function in Different Types of Muscle Tissues in Health and Disease

“…Interestingly, pharmacological inhibition of mtCU restores the levels of autophagy and mitophagy, partially prevents both the cardiomyocytes hypertrophy and myocardial fibrosis, and alleviates the concomitant ventricular asynchrony [103]. On the other hand, correction of cardiac dysfunction by cardiac resynchronization therapy provides mitochondrial fission and autophagosome/mitophagosome formation underlying the alleviated cell enlargement and myocardial fibrosis [124]. This therapeutic approach leads to a significant reduction in MCU and p62 content accompanied by DRP1 upregulation [124], which brings up an important question of mtCU participation in the mitochondria quality control.…”

“…On the other hand, correction of cardiac dysfunction by cardiac resynchronization therapy provides mitochondrial fission and autophagosome/mitophagosome formation underlying the alleviated cell enlargement and myocardial fibrosis [124]. This therapeutic approach leads to a significant reduction in MCU and p62 content accompanied by DRP1 upregulation [124], which brings up an important question of mtCU participation in the mitochondria quality control. Cho et al have recently reported that mtCU mediates the DRP1-dependent Zn 2+ influx into the mitochondrial intermembrane space during fission [125].…”