Aldehydic load and aldehyde dehydrogenase 2 profile during the progression of post-myocardial infarction cardiomyopathy: Benefits of Alda-1

Abstract

Background/Objectives We previously demonstrated that reducing cardiac aldehydic load by aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme responsible for metabolizing the major lipid peroxidation product, protects against acute ischemia/reperfusion injury and chronic heart failure. However, time-dependent changes in ALDH2 profile, aldehydic load and mitochondrial bioenergetics during progression of post-myocardial infarction (post-MI) cardiomyopathy is unknown and should be established to determine the optimal time window for drug treatment. Methods Here we characterized cardiac ALDH2 activity and expression, lipid peroxidation, 4-hydroxy-2-nonenal (4-HNE) adduct formation, glutathione pool and mitochondrial energy metabolism and H2O2 release during the 4 weeks after permanent left anterior descending (LAD) coronary artery occlusion in rats. Results We observed a sustained disruption of cardiac mitochondrial function during the progression of post-MI cardiomyopathy, characterized by >50% reduced mitochondrial respiratory control ratios and up to 2 fold increase in H2O2 release. Mitochondrial dysfunction was accompanied by accumulation of cardiac and circulating lipid peroxides and 4-HNE protein adducts and down-regulation of electron transport chain complexes I and V. Moreover, increased aldehydic load was associated with a 90% reduction in cardiac ALDH2 activity and increased glutathione pool. Further supporting an ALDH2 mechanism, sustained Alda-1 treatment (starting 24hrs after permanent LAD occlusion surgery) prevented aldehydic overload, mitochondrial dysfunction and improved ventricular function in post-MI cardiomyopathy rats. Conclusion Taken together, our findings demonstrate a disrupted mitochondrial metabolism along with an insufficient cardiac ALDH2-mediated aldehyde clearance during the progression of ventricular dysfunction, suggesting a potential therapeutic value of ALDH2 activators during the progression of post-myocardial infarction cardiomyopathy.

Translational Implications of the Alcohol-Metabolizing Enzymes, Including Cytochrome P450-2E1, in Alcoholic and Nonalcoholic Liver Disease

“…In fact, Mochly-Rosen and her colleagues identified ALDH2 activators through screening chemical libraries and demonstrated the protective effects of synthetic ALDH2 activators such as alda-1 [N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide], alda-44, and alda-89, which not only restored the suppressed ALDH2 activity but also significantly protected the heart under I/R condition (Budas, Disatnik, Chen, & Mochly-Rosen, 2010;Chen, Budas, et al, 2008). More recent reports showed that alda-1 is cardioprotective in post-myocardial infarction (Gomes et al, 2015) or in aged mice as well as hepatoprotective against alcoholinduced steatosis and cell death (Zhong et al, 2014). These results clearly demonstrate that ALDH2 could become a new, emerging target for developing medicines not only for treating cardiovascular diseases but also for other tissues including the liver and brain (Luo, Liu, Ma, & Peng, 2014).…”

Disruption of mitochondrial quality control in peripheral artery disease: New therapeutic opportunities

“…4-HNE is a highly reactive aldehyde that irreversibly forms protein adducts via Michael addition or Schiff base reaction (99). Excessive 4-HNE adducts formation has been previously reported in ischemic hearts from both humans and rodents (100) and was associated with contractility dysfunction and impaired mitochondrial bioenergetics (33, 97, 98). Increased 4-HNE-modified proteins have also been reported in gastrocnemius muscle biopsies from individual with PAD and rodents subjected to hindlimb ischemia (28, 101, 102).…”

“…4-hydroxy-2-nonenal (4-HNE), a secondary end-product of lipid peroxidation, negatively affects mitochondrial function during ischemic events (33, 97, 98). 4-HNE is a highly reactive aldehyde that irreversibly forms protein adducts via Michael addition or Schiff base reaction (99).…”

“…Among 19 functional ALDH genes, the mitochondrial aldehyde dehydrogenase 2 (ALDH2) has emerged as a key enzyme in protecting against mitochondrial dysfunction and oxidative stress (33, 98, 103, 104). ALDH2, a tetrameric enzyme located in the mitochondrial matrix, is responsible for catalyzing the convergence of the highly reactive 4-HNE and short-chain aliphatic aldehydes into inactive acids (103, 105).…”

“…Moreover, selective ALDH2 activation using a small molecule (Alda-1) protects against cardiac ischemia-reperfusion injury and heart failure (97, 103). The ALDH2-mediated cardioprotection involves improved mitochondrial bioenergetics and reduced both aldehydic overload and oxidative stress (33, 97). This scenario provides evidence that ALDH2-mediated removal of toxic aldehydes is a critical mitochondrial quality control mechanism thus protecting against cardiac ischemia-reperfusion injury (73).…”