Aldehyde Dehydrogenase 2 Protects Against Lipopolysaccharide-Induced Myocardial Injury by Suppressing Mitophagy.

Wenqing Ji,Tiantian Wan,Xiaomei Zhu,Xue Mei,Shubin Guo,Fang Zhang

doi:10.3389/fphar.2021.641058

Abstract

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis-induced circulatory and cardiac dysfunction is associated with high mortality rates. Mitophagy, a specific form of autophagy, is excessively activated in lipopolysaccharide-induced myocardial injury. The present study investigated whether aldehyde dehydrogenase 2 (ALDH2) regulates mitophagy in sepsis-induced myocardial dysfunction. After lipopolysaccharide administration, cardiac dysfunction, inflammatory cell infiltration, biochemical indicators of myocardial cell injury, and cardiomyocyte apoptosis were ameliorated in mice by ALDH2 activation or overexpression. In contrast, cardiac dysfunction and cardiomyocyte apoptosis were exacerbated in mice followed ALDH2 inhibition. Moreover, ALDH2 activation or overexpression regulated mitophagy by suppressing the expression of phosphatase and tensin homolog-induced putative kinase 1 (PINK1)/Parkin, by preventing the accumulation of 4-hydroxy-trans-nonenal. Conversely, ALDH2 inhibition promoted the expression of LC3B by increasing 4-hydroxy-trans-2-nonenal accumulation. Consequently, ALDH2 may protect the heart from lipopolysaccharide-induced injury by suppressing PINK1/Parkin-dependent mitophagy.

Highlights

The cardiovascular system is a major target of sepsis, which is a systemic inflammatory response that can induce organ dysfunction (Annane et al, 2005) and is the leading cause of in-hospital mortality (Liu et al, 2014)
There were no significant differences in LVPWd, left ventricular mass, and LVIDd among the groups (Figures 1E–G)
We found that ALDH2 activation or overexpression could counteract sepsis-associated cardiac injury in vivo by FIGURE 5 | 4-Hydroxy-trans-2-nonenal (4HNE) accumulation, aldehyde dehydrogenase 2 (ALDH2) activity and expression, and ultrastructural changes in lipopolysaccharide (LPS)-treated mice (A,B) Representative western blots and quantification analysis of 4HNE and glyceraldehyde 3-phosphate dehydrogenase (GAPDH; loading control). (C) Representative western blots and quantification analysis of ALDH2 and GAPDH. (D) Quantification of ALDH2 enzymatic activity. (E) Representative transmission electron microscopy (TEM) images from four mouse groups

Summary

Introduction

The cardiovascular system is a major target of sepsis, which is a systemic inflammatory response that can induce organ dysfunction (Annane et al, 2005) and is the leading cause of in-hospital mortality (Liu et al, 2014). There is no effective treatment for sepsis-related cardiac dysfunction. The mechanisms underlying sepsis-induced myocardial damage are related to a number of different processes, including mitochondrial dysfunction, oxidative stress, cardiomyocyte apoptosis, direct effects of bacterial toxins, calcium dyshomeostasis, and impaired β-adrenaline signaling (Suffredini et al, 1989; Chen et al, 2003; Drosatos et al, 2015; Hobai et al, 2015; Zhao et al, 2016). Mitochondrial dysfunction plays a dominant role in the development and progression of cardiac dysfunction in sepsis (Chen et al, 2003)

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Conclusion