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Cyclophosphamide (CY)-induced acute cardiotoxicity is a common side effect which is dose dependent. It is reported that up to 20% of patients received high dose of CY treatment suffered from acute cardiac dysfunction. However, the effective intervention strategies and related mechanisms are still largely unknown. We aimed to investigate the effects of aldehyde dehydrogenase 2 (ALDH2), an important endogenous cardioprotective enzyme, on CY-induced acute cardiotoxicity and the underlying mechanisms. It was found that ALDH2 knockout (KO) mice were more sensitive to CY-induced acute cardiotoxicity, presenting as higher serum levels of creatine kinase-MB isoform and lactate dehydrogenase, and significantly reduced myocardial contractility compared with C57BL/6 (WT) mice. In addition, cardiac cell death, especially necrosis, was obviously increased in ALDH2 KO mice compared with WT mice after CY treatment. Furthermore, accumulation of toxic aldehydes such as acrolein and 4-HNE and reactive oxygen species (ROS) in the myocardium were significantly elevated after CY in ALDH2 KO mice. Importantly, ALDH2 activation by Alda-1 pretreatment markedly attenuated CY-induced accumulation of toxic aldehydes, cardiac cell death and cardiac dysfunction, without affecting CY's anti-tumor efficacy. In conclusion, the cardioprotective effects of ALDH2 activation against CY-induced acute cardiotoxicity are exerted via reducing toxic aldehydes accumulation and potentially interrupting the acrolein-ROS-aldehydes vicious circles, and thus alleviates myocardial cell death, without antagonizing the anti-tumor efficacy of CY. Therefore, ALDH2 might be a promising prevention and treatment target for CY-induced acute cardiotoxicity. [ABSTRACT FROM AUTHOR]

Many studies have shown that mitochondrial aldehyde dehydrogenase 2 (ALDH2) functions as a cellular protector against oxidative stress by detoxification of cytotoxic aldehydes. Within dopaminergic neurons, dopamine is metabolized by monoamine oxidase to yield 3,4-dihydroxyphenylacetaldehyde (DOPAL) then converts to a less toxic acid product by ALDH. The highly toxic and reactive DOPAL has been hypothesized to contribute to the selective neurodegeneration in Parkinson's disease (PD). In this study, we investigated the neuroprotective mechanism and therapeutic effect of ALDH2 in rotenone models for parkinsonism. Overexpression of wild-type ALDH2 gene, but not the enzymatically deficient mutant ALDH2*2 (E504K), reduced rotenone-induced cell death. Application of a potent activator of ALDH2, Alda-1, was effective in protecting against rotenone-induced apoptotic cell death in both SH-SY5Y cells and primary cultured substantia nigra (SN) dopaminergic neurons. In addition, intraperitoneal administration of Alda-1 significantly reduced rotenone- or MPTP-induced death of SN tyrosine hydroxylase (TH)-positive dopaminergic neurons. The attenuation of rotenone-induced apoptosis by Alda-1 resulted from decreasing ROS accumulation, reversal of mitochondrial membrane potential depolarization, and inhibition of activation of proteins related to mitochondrial apoptotic pathway. The present study demonstrates that ALDH2 plays a crucial role in maintaining normal mitochondrial function to protect against neurotoxicity and that Alda-1 is effective in ameliorating mitochondrial dysfunction and inhibiting mitochondria-mediated apoptotic pathway. These results indicate that ALDH2 activation could be a neuroprotective therapy for PD. [ABSTRACT FROM AUTHOR]

Abstract: Aging process results from deleterious damages by reactive oxygen species, in particular, various metabolic aldehydes. Aldehyde dehydrogenase 2 (ALDH2) is one of metabolic enzymes detoxifying various aldehydes under oxidative conditions. AMP-activated protein kinase (AMPK) plays a key role in controlling metabolic process. However, little was known about the relationship of ALDH2 with AMPK under oxidative conditions. Here, we, by using MDA-specific monoclonal antibody, screened the tissues of young and old rats for MDA-modified proteins and identified an ALDH2 as a prominent MDA-modified protein band in the old rat kidney tissue. ALDH2 associates with AMPK and is phosphorylated by AMPK. In addition, AICAR, an activator of AMP-activated protein kinase, induces the nuclear translocation of ALDH2. ALDH2 in nucleus is involved in general transcription repression by association with histone deacetylases. Furthermore, MDA modification inhibited the translocation of ALDH2 and the association with AMPK, and ultimately led to de-repression of transcription in the reporter system analysis. In this study, we have demonstrated that ALDH2 acts as a transcriptional repressor in response to AMPK activation, and MDA modifies ALDH2 and inhibits repressive activity of ALDH2 in general transcription. We thus suggest that increasing amount of MDA during aging process may interrupt the nuclear function of ALDH2, modulated by AMPK. [ABSTRACT FROM AUTHOR]