| 1 | ALDH2 contributes to melatonin-induced protection against APP/PS1 mutation-prompted cardiac anomalies through cGAS-STING-TBK1-mediated regulation of mitophagy显示文摘Ample clinical evidence suggests a high incidence of cardiovascular events in Alzheimer’s disease(AD),although neither precise etiology nor effective treatment is available.This study was designed to evaluate cardiac function in AD patients and APP/PS1 mutant mice,along with circulating levels of melatonin,mitochondrial aldehyde dehydrogenase(ALDH2)and autophagy.AD patients and APP/PS1 mice displayed cognitive and myocardial deficits,low levels of circulating melatonin,ALDH2 activity,and autophagy,ultrastructural,geometric(cardiac atrophy and interstitial fibrosis)and functional(reduced fractional shortening and cardiomyocyte contraction)anomalies,mitochondrial injury,cytosolic mtDNA buildup,apoptosis,and suppressed autophagy and mitophagy.APP/PS1 mutation downregulated cyclic GMP-AMP synthase(cGAS)and stimulator of interferon genes(STING)levels and TBK1 phosphorylation,while promoting Aβaccumulation.Treatment with melatonin overtly ameliorated unfavorable APP/PS1-induced changes in cardiac geometry and function,apoptosis,mitochondrial integrity,cytosolic mtDNA accumulation(using both immunocytochemistry and qPCR),mitophagy,and cGAS-STING-TBK1 signaling,although these benefits were absent in APP/PS1/ALDH2−/−mice.In vitro evidence indicated that melatonin attenuated APP/PS1-induced suppression of mitophagy and cardiomyocyte function,and the effect was negated by the nonselective melatonin receptor blocker luzindole,inhibitors or RNA interference of cGAS,STING,TBK1,and autophagy.Our data collectively established a correlation among cardiac dysfunction,low levels of melatonin,ALDH2 activity,and autophagy in AD patients,with compelling support in APP/PS1 mice,in which melatonin rescued myopathic changes by promoting cGAS-STING-TBK1 signaling and mitophagy via an ALDH2-dependent mechanism. | Shuyi Wang Lin Wang Xing Qin Subat Turdi Dongdong Sun Bruce Culver Russel JReiter Xiaoming Wang Hao Zhou Jun Ren | 2020 | Signal Transduction and Targeted Therapy2020，5，1： | 9 |
| 2 | Mitochondrial aldehyde dehydrogenase(ALDH2)rescues cardiac contractile dysfunction in an APP/PS1 murine model of Alzheimer’s disease via inhibition of ACSL4-dependent ferroptosis显示文摘Alzheimer’s disease(AD)is associated with high incidence of cardiovascular events but the mechanism remains elusive.Our previous study reveals a tight correlation between cardiac dysfunction and low mitochondrial aldehyde dehydrogenase(ALDH2)activity in elderly AD patients.In the present study we investigated the effect of ALDH2 overexpression on cardiac function in APP/PS1 mouse model of AD.Global ALDH2 transgenic mice were crossed with APP/PS1 mutant mice to generate the ALDH2-APP/PS1 mutant mice.Cognitive function,cardiac contractile,and morphological properties were assessed.We showed that APP/PS1 mice displayed significant cognitive deficit in Morris water maze test,myocardial ultrastructural,geometric(cardiac atrophy,interstitial fibrosis)and functional(reduced fractional shortening and cardiomyocyte contraction)anomalies along with oxidative stress,apoptosis,and inflammation in myocardium.ALDH2 transgene significantly attenuated or mitigated these anomalies.We also noted the markedly elevated levels of lipid peroxidation,the essential lipid peroxidation enzyme acyl-CoA synthetase long-chain family member 4(ACSL4),the transcriptional regulator for ACLS4 special protein 1(SP1)and ferroptosis,evidenced by elevated NCOA4,decreased GPx4,and SLC7A11 in myocardium of APP/PS1 mutant mice;these effects were nullified by ALDH2 transgene.In cardiomyocytes isolated from WT mice and in H9C2 myoblasts in vitro,application of Aβ(20μM)decreased cell survival,compromised cardiomyocyte contractile function,and induced lipid peroxidation;ALDH2 transgene or activator Alda-1 rescued Aβ-induced deteriorating effects.ALDH2-induced protection against Aβ-induced lipid peroxidation was mimicked by the SP1 inhibitor tolfenamic acid(TA)or the ACSL4 inhibitor triacsin C(TC),and mitigated by the lipid peroxidation inducer 5-hydroxyeicosatetraenoic acid(5-HETE)or the ferroptosis inducer erastin.These results demonstrate an essential role for ALDH2 in AD-induced cardiac anomalies through regulation of lipid peroxidation and ferroptosis. | Zhi-yun Zhu Yan-dong Liu Yan Gong Wei Jin Elena Topchiy Subat Turdi Yue-feng Gao Bruce Culver Shu-yi Wang Wei Ge Wen-liang Zha Jun Ren Zhao-hui Pei Xing Qin | 2022 | Acta Pharmacologica Sinica2022，43，1： | 6 |
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