Simultaneous Suppression of Multiple Programmed Cell Death Pathways by miRNA-105 in Cardiac Ischemic Injury

Sunhye Shin,Jung-Won Choi,Hanbyeol Moon,Chang Youn Lee,Jun-Hee Park,Jiyun Lee,Hyang-Hee Seo,Gyoonhee Han,Soyeon Lim,Seahyoung Lee,Sang Woo Kim,Ki-Chul Hwang

doi:10.1016/j.omtn.2018.12.015

Abstract

Recent studies have shown that several upstream signaling elements of apoptosis and necroptosis are closely associated with acute injury in the heart. In our study, we observed that miR-105 was notably dysregulated in rat hearts with myocardial infarction (MI). Thus, the purpose of this study was to test the hypothesis that miR-105 participates in the regulation of RIP3/p-MLKL- and BNIP3-dependent necroptosis/apoptosis in H9c2 cells and MI rat hearts. Our results show that the RIP3/p-MLKL necroptotic pathway and BNIP3-dependent apoptosis signaling are enhanced in H9c2 cells under hypoxic conditions, whereas, compared with these pathways in the controls, those in miR-105-treated H9c2 cells are suppressed. Mechanistically, we identified miR-105 as the miRNA directly suppressing the expression of RIP3 and BNIP3, two important mediators involved in cell necroptosis and apoptosis. Furthermore, MI rat hearts injected with miR-105 had decreased infarct sizes, indicating that miR-105 is among three miRNAs that function simultaneously to suppress necroptotic/apoptotic cell death pathways and to inhibit MI-induced cardiomyocyte cell death at multiple levels. Taken together, miR-105 may constitute a new therapeutic strategy for cardioprotection in ischemic heart disease.

Highlights

Necroptosis is another regulated cell death mechanism that exists in various diseases, including myocardial infarction (MI), ischemia reperfusion (I/R) injury, heart failure, and inflammation,[11,12] and it is regulated by the necrosome, which consists of receptor-interacting protein kinase 3 (RIP3) and mixed lineage kinase-like (MLKL).[9]
Apoptosis and Necroptosis of Rat Heart following Myocardial Ischemia and MI First, we investigated the types of cell death distributed in the heart after MI (Figure 1)
Western blot analysis showed that the levels of indicators of apoptosis (CASP3, caspase 8, and BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 (BNIP3)) and necroptosis (RIP3 and p-MLKL) were significantly increased in hearts after MI (Figure 1C)

Summary

Introduction

Heart disease, including heart failure, myocardial infarction (MI), and ischemia reperfusion (I/R), is one of the causes of mortality and morbidity worldwide.[1,2,3,4] Numerous studies have demonstrated that MI and I/R injuries lead to various types of cardiomyocyte cell death (e.g., necrosis, apoptosis, and autophagy).[5,6] For many years, apoptosis was considered the only form of regulated cell death, according to studies investigating myocyte cell death; apoptosis is a well-established programmed form of cell death that can be initiated by a mitochondria-mediated intrinsic pathway and death-receptormediated extrinsic pathway.[5,7] The programmed form of cell death has been described as an “unregulated” or “accidental” form of cell death. The initiation of necroptosis is triggered by death ligands, such as tumor necrosis factor (TNF)-a, TNF-related apoptosis inducing ligand (TRAIL), and pathogen-associated molecular patterns (PAMPs).[10]

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