Vitamin D Attenuates Ischemia/Reperfusion-Induced Cardiac Injury by Reducing Mitochondrial Fission and Mitophagy.

Tzu-Lin Lee,Lee-Fen Hsu,Yi-Chieh Lee,Chiang-Wen Lee,Hugo You-Hsien Lin,Tsai-Chun Lai,Yuh-Lien Chen,Hsin-Ching Sung,Yu-Chen Chen,Ming-Hsueh Lee

doi:10.3389/fphar.2020.604700

Abstract

Myocardial infarction is the leading cause of morbidity and mortality worldwide. Although myocardial reperfusion after ischemia (I/R) is an effective method to save ischemic myocardium, it can cause adverse reactions, including increased oxidative stress and cardiomyocyte apoptosis. Mitochondrial fission and mitophagy are essential factors for mitochondrial quality control, but whether they play key roles in cardiac I/R injury remains unknown. New pharmacological or molecular interventions to alleviate reperfusion injury are currently considered desirable therapies. Vitamin D3 (Vit D3) regulates cardiovascular function, but its physiological role in I/R-exposed hearts, especially its effects on mitochondrial homeostasis, remains unclear. An in vitro hypoxia/reoxygenation (H/R) model was established in H9c2 cells to simulate myocardial I/R injury. H/R treatment significantly reduced H9c2 cell viability, increased apoptosis, and activated caspase 3. In addition, H/R treatment increased mitochondrial fission, as manifested by increased expression of phosphorylated dynein-related protein 1 (p-Drp1) and mitochondrial fission factor (Mff) as well as increased mitochondrial translocation of Drp1. Treatment with the mitochondrial reactive oxygen species scavenger MitoTEMPO increased cell viability and decreased mitochondrial fission. H/R conditions elicited excessive mitophagy, as indicated by increased expression of BCL2-interacting protein 3 (BNIP3) and light chain (LC3BII/I) and increased formation of autolysosomes. In contrast, Vit D3 reversed these effects. In a mouse model of I/R, apoptosis, mitochondrial fission, and mitophagy were induced. Vit D3 treatment mitigated apoptosis, mitochondrial fission, mitophagy, and myocardial ultrastructural abnormalities. The results indicate that Vit D3 exerts cardioprotective effects against I/R cardiac injury by protecting mitochondrial structural and functional integrity and reducing mitophagy.

Highlights

The World Health Organization (WHO) reports that acute myocardial infarction is the leading cause of morbidity and mortality in many regions of the world (Roth et al, 2017)
To evaluate whether Vit D pretreatment improves myocardial cell damage under I/R conditions, H9c2 cells were pretreated with Vit D or PBS and subjected to H/R in vitro to simulate the physiological stress experienced by cardiomyocytes during ischemic infarct
The important findings we report are that exogenous Vit D treatment can 1) reduce cardiomyocyte apoptosis and reactive oxygen species (ROS) production; 2) increase mitochondrial membrane potential; 3) reduce mitochondrial fission via decreased Drp1 and mitochondrial fission factor (Mff) expression; and 4) reduce mitophagy by reducing the H/R-induced expression of BCL2-interacting protein 3 (BNIP3) and LC3B

Summary

Introduction

The World Health Organization (WHO) reports that acute myocardial infarction is the leading cause of morbidity and mortality in many regions of the world (Roth et al, 2017). I/R injury is a multifactorial pathophysiological process that causes cell damage during hypoxia, and the damage becomes more severe when oxygen is re-delivered into the tissue (Rossello et al, 2018). I/R causes a series of adverse events, such as excessive reactive oxygen species (ROS) production, calcium overload, inflammatory responses, increased apoptosis, and mitochondrial dysfunction, all of which lead to myocardial cell death and accelerate myocardial damage (Yellon and Hausenloy, 2007). New pharmacological or molecular interventions that alleviate reperfusion injury are highly desirable for current reperfusion therapy (Baehr et al, 2019; Yu et al, 2019)

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