Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitochondrial aldehyde dehydrogenase (ALDH2) is an isoenzyme of aldehyde dehydrogenases (ALDH), a group of enzymes that are responsible for clearance of aldehydes in the body. In animal myocardial or cerebral ischemia/ reperfusion (I/R) models, accumulation of toxic aldehydes, such as 4-hydroxy-2-nonenal and malondialdehyde, is thought to be an important mechanism for myocardial and cerebral I/R injury. Among the isoenzymes of ALDH, ALDH2 is believed to play a major role in clearance of toxic aldehydes. Thus, ALDH2 might be a potential drug target for protection of the heart or brain from I/R injury. Indeed, some of the newly identified ALDH2 activators (such as Alda-1) have demonstrated beneficial effects on heart and brain I/R injury. In addition, ALDH activity is present at high levels in some stem or progenitor cells, known as ALDH bright (ALDH(br)) cells, which possess potential value in treating patients with myocardial ischemia. The main purpose of this review is 1) to summarize recent findings regarding the role of ALDH2 in protection of heart or brain from I/R injury, 2) to list the available ALDH2 activators with their potency, selectivity and clinical potentials, and 3) to provide a rationale for ALDH(br) cells in clinical therapeutic value.
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PMID:Mitochondrial aldehyde dehydrogenase, a potential drug target for protection of heart and brain from ischemia/reperfusion injury. 2516 52

Acute myocardial infarction is one of the major causes of mortality worldwide. Reperfusion in a timely fashion is the most effective way to limit infarct size. However, reperfusion can itself prompt further myocardial injury. This phenomenon is commonly known as myocardial ischemia-reperfusion (IR) injury. Mitochondrial aldehyde dehydrogenase (ALDH2) is an enzyme metabolizing acetaldehyde and toxic aldehydes. Increasing evidence has revealed a cardioprotective role of ALDH2 in myocardial IR injury. Evidence from animal studies has shown that ALDH2 diminishes acute myocardial infarct size, ameliorates cardiac dysfunction and prevents reperfusion arrhythmias. The activity of ALDH2 is severely compromised if it is encoded by the mutant ALDH2*2 gene, with an incidence of approximately 40% in Asian populations. Epidemiological surveys in the Asian population have depicted that ALDH2 polymorphism is closely associated with higher prevalence of acute myocardial infarction and coronary artery disease. Therefore, targeting ALDH2 may represent a promising avenue to protect against IR injury. This review recapitulates the underlying mechanisms involved in the protective effect of ALDH2 in cardiac IR injury. Translational potential of ALDH2 in the management of coronary heart disease is also discussed.
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PMID:Mitochondrial aldehyde dehydrogenase in myocardial ischemia-reperfusion injury: from bench to bedside. 2670 29

Clinical observations have demonstrated a link between chronic pain and increased ischemic heart disease mortality, but the mechanisms remain elusive. Reactive aldehydes have recently been confirmed as a new player in pain pathologies, while our previous study demonstrated that reactive aldehydes (4-HNE) induced carbonyl stress contributing to myocardial ischemic intolerance. The aim of this study was to explore whether chronic pain increases susceptibility to myocardial ischemia/reperfusion (MI/R) injury and to investigate the underlying mechanisms focusing on toxic aldehyde and carbonyl stress. Methods: Chronic pain was induced by chronic compression of the dorsal root ganglion (CCD). After 2 weeks CCD, aldehyde dehydrogenase (ALDH2) KO or wild-type (WT) littermate mice were then subjected to in vivo MI/R. Results: In CCD-WT mice, heightened nociception paralleled circulating aldehyde (4-HNE) accumulation and cardiac protein carbonylation. Mechanistically, CCD-induced 4-HNE overload provoked cardiac Sirtuin 1 (SIRT1) carbonylative inactivation and inhibited Liver kinase B1 (LKB1) - AMP-activated protein kinase (LKB1-AMPK) interaction, which resulted in exacerbated MI/R injury and higher mortality compared with non-CCD WT mice. ALDH2 deficiency further aggravated CCD-induced susceptibility to MI/R injury. Exogenous 4-HNE exposure in peripheral tissue mimicked chronic pain-induced aldehyde overload, elicited sustained allodynia and increased MI/R injury. However, cardiac-specific ALDH2 upregulation by AAV9-cTNT-mediated gene delivery significantly ameliorated chronic pain-induced SIRT1 carbonylative inactivation and decreased MI/R injury (minor infarct size, less apoptosis, and improved cardiac function). Conclusion: Collectively, chronic pain-enhanced carbonyl stress promotes myocardial ischemic intolerance by SIRT1 carbonylative inactivation and impairment of LKB1-AMPK interaction. ALDH2 activation and prevention of protein carbonylation may be a potential therapeutic target for myocardial ischemic vulnerability in chronic pain patients. Our results newly provided overlapping cellular mechanisms of chronic pain and myocardial dysfunction interplay.
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PMID:Targeting ALDH2 for Therapeutic Interventions in Chronic Pain-Related Myocardial Ischemic Susceptibility. 2946 97

Myocardial ischemia-reperfusion (IR) injury during acute myocardial infarction or open-heart surgery would promote oxidative stress, leading to the accumulation of reactive aldehydes that cause cardiac damage. It has been well demonstrated that aldehyde dehydrogenase (ALDH)-2 is an important cardioprotective enzyme for its central role in the detoxification of reactive aldehydes. ALDH2 activation by small molecule activators is a promising approach for cardioprotection for myocardial IR injury.
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PMID:Mitochondrial Aldehyde Dehydrogenase in Myocardial Ischemic and Ischemia-Reperfusion Injury. 3136

Coronary spasm plays an important role in the pathogenesis of ischemic heart disease, including angina pectoris, acute myocardial infarction (AMI), silent myocardial ischemia, and sudden death. The prevalence of coronary spasm is higher among East Asians probably due to genetic as well as environmental factors. ALDH2 eliminates toxic aldehydes including 4-hydroxy-2-nonenal (4-HNE) derived from lipid peroxidation and acrolein in tobacco smoking as well as ethanol-derived acetaldehyde and thereby protects tissues and cells from oxidative damage. Deficient variant ALDH2*2 genotype is prevalent among East Asians and is a significant risk factor for both coronary spasm and AMI through accumulation of toxic aldehydes, thereby contributing to oxidative stress, endothelial damage, vasoconstriction, and thrombosis. Toxic aldehydes are thus identified as risk factors to be targeted for the treatment of coronary spasm and AMI.
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PMID:Association of East Asian Variant Aldehyde Dehydrogenase 2 Genotype (ALDH2*2*) with Coronary Spasm and Acute Myocardial Infarction. 3136 1