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

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.

Dysregulated autophagy-related genes in septic cardiomyopathy: Comprehensive bioinformatics analysis based on the human transcriptomes and experimental validation

“…GSEA identified widespread dysregulation of ARGs in septic hearts, which corroborates with previous studies, suggesting that dysregulated autophagy may be an important pathological mechanism in SCM ( 60 , 61 ). GO enrichment analysis further reveals the biological processes, cellular component localization, and molecular functions of ARGs in SCM.…”

Aldehyde Dehydrogenase 2 (ALDH2) Elicits Protection against Pulmonary Hypertension via Inhibition of ERK1/2-Mediated Autophagy

“…Coherent to the previous studies, we demonstrated that the triggering of autophagy was involved in PASMC migration and proliferation. ALDH2 was reported to attenuate cardiovascular diseases through the regulation of autophagy including heart failure [ 16 ], diabetic cardiomyopathy [ 51 ], and myocardial dysfunction [ 52 ]. However, most studies emphasized on the direct detoxification properties of ALDH2 instead of its interactions with autophagy, especially in the scenario of PH.…”

Mitochondria-endoplasmic reticulum contacts in sepsis-induced myocardial dysfunction

“…In H9c2 cells, activation of the PINK1/Parkin pathway is also found to attenuate mitochondrial damage, oxidative stress, and apoptosis induced by LPS treatment (Bin et al, 2021). However, Ji et al Ji et al (2021) Another study also shows that the level of FUNDC1 is significantly increased in LPS-induced myocardial injury, and improvement in myocardial injury is accompanied by a decrease in FUDNC1 levels (Ji et al, 2021). In conclusion, MERCs-associated mitophagy plays an important role in SIMD, but its specific effects need to be further elucidated.…”

“…In H9c2 cells, activation of the PINK1/Parkin pathway is also found to attenuate mitochondrial damage, oxidative stress, and apoptosis induced by LPS treatment ( Bin et al, 2021 ). However, Ji et al Ji et al (2021) find that PINK1/Parkin-dependent mitophagy aggravates sepsis-induced myocardial injury. Rahim et al Rahim et al (2021) and Jiang et al Jiang et al (2021a) also show that the levels of PINK-1/Parkin signaling are greatly increased in sepsis-induced heart injury.…”