Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
J Cell Mol Med. 2012 Mar;16(3):616-26. doi: 10.1111/j.1582-4934.2011.01347.x.
Mitochondrial aldehyde dehydrogenase-2 (ALDH2) has been shown to benefit myopathic changes following alcohol intake, although the precise mechanism is still unclear. This study was designed to evaluate the role of ALDH2 on chronic alcohol intake-induced myocardial geometric and functional damage with a focus on autophagic signalling. Wild-type friendly virus B (FVB) and transgenic mice overexpressing ALDH2 driven by chicken β-actin promoter were fed a 4% alcohol liquid diet for 12 weeks. Cardiac geometry and function were assessed using echocardiographic and IonOptix systems. Western blot analysis was used to evaluate the essential autophagy markers, Akt and AMP-dependent protein kinase (AMPK) as well as their downstream signalling mammalian target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3). Alcohol intake altered cardiac geometry and function as demonstrated by lessened LV wall and septal thickness, enlarged end systolic and diastolic diameters, decreased fractional shortening and cell shortening, the effects of which were mitigated by ALDH2 transgene. Chronic alcohol intake triggered myocardial autophagy as shown by LC3B II isoform switch, as well as decreased phosphorylation of mTOR, the effects of which were ablated by ALDH2. Chronic alcohol intake suppressed phosphorylation of Akt and AMPK, which was reconciled by ALDH2. Levels of Notch1 and STAT3 phosphorylation were dampened by chronic alcohol intake in FVB but not ALDH2 myocardium. Moreover, the γ-secretase Notch inhibitor N\xE2\x80\x90[N-(3,5-difluorophenacetyl)-1-alany1]-S-phenyglycine t-butyl ester exacerbated ethanol-induced cardiomyocyte contractile dysfunction, apoptosis and autophagy. In summary, these findings suggested that ALDH2 elicits cardioprotection against chronic alcohol intake-induced cardiac geometric and functional anomalies by inhibition of autophagy possibly via restoring the Akt-mTOR-STAT3-Notch signalling cascade.
线粒体乙醛脱氢酶 2（ALDH2）已被证明可改善饮酒后的肌病变化，尽管确切机制仍不清楚。本研究旨在评估 ALDH2 在慢性酒精摄入诱导的心肌几何和功能损伤中的作用，重点关注自噬信号。野生型友好病毒 B（FVB）和转基因小鼠过表达由鸡 β-肌动蛋白启动子驱动的 ALDH2，用 4%酒精液体饮食喂养 12 周。使用超声心动图和 IonOptix 系统评估心脏几何形状和功能。Western blot 分析用于评估必需的自噬标志物、Akt 和 AMP 依赖性蛋白激酶（AMPK）及其下游信号哺乳动物雷帕霉素靶蛋白（mTOR）和信号转导和转录激活因子 3（STAT3）。酒精摄入改变了心脏几何形状和功能，表现为 LV 壁和室间隔厚度减小，舒张末期和收缩末期直径增大，缩短分数和细胞缩短减小，这些影响被 ALDH2 转基因减轻。慢性酒精摄入触发心肌自噬，表现为 LC3B II 同工型转换，以及 mTOR 磷酸化减少，这些影响被 ALDH2 消除。慢性酒精摄入抑制 Akt 和 AMPK 的磷酸化，而 ALDH2 则使这种抑制得到缓解。慢性酒精摄入降低了 FVB 心肌中的 Notch1 和 STAT3 磷酸化水平，但在 ALDH2 心肌中没有降低。此外，γ-分泌酶 Notch 抑制剂 N-[（3,5-二氟苯乙酰基）-1-丙氨酸]-S-苯甘氨酸叔丁酯加剧了乙醇诱导的心肌细胞收缩功能障碍、凋亡和自噬。总之，这些发现表明，ALDH2 通过抑制自噬来发挥心脏保护作用，防止慢性酒精摄入引起的心脏几何和功能异常，可能通过恢复 Akt-mTOR-STAT3-Notch 信号级联来实现。
