The Anti-Arrhythmic Potential of Aldehyde Dehydrogenase 2

Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme considered as a key detoxifying enzyme in alcohol metabolism. In recent years, ALDH2 has been recognized as a protector against oxidative stress, ischemic-reperfusion injury (I/R), and arrhythmias in the heart. The review paper by Jin et al.¹ in this issue focused on our current understanding of the protective role of ALDH2 in cardiac arrhythmias and the therapeutic potential.

ALDH2 is a predominant cardiac isoform for preventing the accumulation of acetaldehyde. A key function of ALDH2 is to catalyze the chemical transformation of toxic reactive aldehydes to carboxylic acids. While reactive aldehydes such as 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) occur in lipid/carbohydrate metabolism, other reactive aldehydes, such as acetaldehyde, can arise from insults like alcohol metabolism and environmental stressors. Jin et al. broadly reviewed the functional roles of aldehydes as risk factors for cardiovascular disease (CVD) due to their many toxic activities including oxidative modification of enzymes, energy production inhibition due to a damaged electron transfer chain, dysregulation of cardiac ion channel functions and cardiac arrhythmogenesis. More specifically, the potential molecular and cellular mechanisms of how ALDH2 acts to alleviate a pro-arrhythmia burden was discussed.

A high myocardial workload increases mitochondria Ca²⁺ entry leading to reactive oxygen species (ROS) overproduction that consequently promotes sarcoplasmic reticulum (SR) Ca²⁺ mishandling and enhances arrhythmogenicity. Interestingly, ALDH2 was found to lower ROS and maintain a normal balance of Ca²⁺ hemostasis. It is well-known that a normal Ca²⁺ homeostasis in myocytes is fundamental for contractile function, while Ca²⁺ mishandling, including SR Ca²⁺ leak and overload may impair myocardial contractility and promote triggered arrhythmic activities. To this point, calcium/calmodulin-dependent protein kinase II (CaMKII), a proarrhythmic kinase regulating multiple Ca²⁺ handling proteins including but not limited to phospholamban (PLB) and the ryanodine receptor (RyR), can be activated via oxidation in high ROS conditions and acts as a cellular redox sensor. ALDH2 is shown to effectively decrease the level of ROS, reduce CaMKII activation and the arrhythmia burden,² suggesting an anti-arrhythmic role of ALDH2 via a maintained redox balance. A stabilizing effect of ALDH2 on cardiac mast cells during myocardial (I/R) injury (aldehyde/ROS challenge), protects from degranulation and renin release in response to aldehydes, which in turn alleviates norepinephrine release via the renin-angiotensin-aldosterone axis to reduce the severity of I/R injury as well as the triggered arrhythmia burden. Thus, the multi-fold protective effects of ALDH2 in the heart deem it a promising therapeutic target in high ROS conditions including I/R injury.

Given the vital role of ALDH2 in alcohol metabolism, its cardiac protective role in alcoholic cardiomyopathy has also been recognized. Alcohol cardiomyopathy is common among chronic drinkers and manifests in reduced contractile dysfunction and cardiac hypertrophy, with acetaldehyde accumulation as a proposed mechanism. The overexpression of ALDH2 in a murine model or long-term treatment of Alda-1 (an activator of ALDH2) showed protective effects in chronic alcoholic animal models evidenced from reduced myocardial hypertrophy and contractile defects.³ However, a well-defined role of ALDH2 in alcohol-evoked cardiac arrhythmias has not been fully explored.

Episodes of excessive alcohol drinking in a relatively brief period of time can induce cardiac arrhythmias in individuals with no prior history of cardiovascular disease. This excessive binge drinking often occurring during holidays and weekends is referred to as “Holiday Heart Syndrome (HHS)”.⁴ HHS patients with significant clinical complaints due to serious heart rhythm abnormalities (i.e., atrial fibrillation) often present in an emergency room after the cessation of several heavy binge alcohol episodes and a baseline blood alcohol concentration (BAC). While acute alcohol damaging period created via aldehydes and ROS, a more gradual progression of molecular and electrophysiological remodeling may occur several hours after the alcohol exposure, and which may only expand upon repeated cycles of acute and excessive alcohol consumption. We recently reported a previously unrecognized causal role of activation of the stress response kinase JNK isoform 2 (JNK2) in driving binge alcohol-evoked atrial arrhythmogenesis in humans, and in animal models of HHS (12–36 hr post-alcohol exposure, zero BAC).^{4, 5} The dual actions of activated JNK2 drives CaMKII-dependent diastolic SR Ca²⁺ leak via JNK2-activated CaMKII and CaMKII-independent SR Ca²⁺ overload by accelerating SR Ca²⁺ uptake due to JNK2-enhanced SERCA2 activity, which results in elevated intracellular Ca²⁺ and enhanced triggered arrhythmic activities.^{4, 5} Here the key arrhythmogenic cause is clearly not due to the immediate aldehyde/ROS insult from metabolized alcohol, but the alcohol-evoked cell signaling alterations with JNK2 acting as a key stress signaling hub. In this case, the JNK2-specific actions in SR Ca²⁺ mishandling occur independently of CaMKII oxidation which is strongly supported by the JNK2-specific activation of CaMKII via enhanced CaMKII phosphorylation. Interestingly, ALDH2 curbs MAPKs activation (JNK, p38 and ERK1/2) in response to alcohol challenge by regulating the redox balance. For example, overexpressing ALDH2 alleviates alcohol toxicity by decreasing the level of ROS and MAPK activation.⁶ The counterbalance of MAPK activity appears to be complex in that direct JNK-mediated phosphorylation of ALDH2 could inhibit its activity but, the contribution of different cardiac isoforms of JNK, especially JNK2, in ALDH2 activities remains to be elucidated.⁶ Future studies on the interplay between ALDH2, MAPKs, and potentially other alcohol and metabolically mediated regulators will be undoubtedly needed to develop our understanding of the mechanisms of alcohol-evoked cardiac arrhythmias and may yield new and effective therapeutic strategies.

Another important aspect reviewed (Jin et al.), implicates ALDH2 as a potential therapeutic target for alcohol and high aldehyde/ROS-evoked cardiac diseases. ALDH2 is not only acting as a reactive aldehyde scavenger but also as a ROS blocker to avert the ROS-mediated cardiac insult. The therapeutic value of ALDH2 activation is also supported by epidemiology data in that impaired ALDH2 activity due to polymorphisms in humans often leads to increased cardiovascular burden at alcohol consumption and for other high stress/ROS situations. Indeed, mouse models carrying ALDH2 mutations also demonstrate that impaired ALDH2 activity often leads to worsened arrhythmia at alcohol consumption and/or high ROS. On the other hand, enhancing ALDH2 activity (use of specific activators as Alda-1 and α-lipoic acid) at high ROS insults alleviates arrhythmia burden. These findings offer important translational potentials of modulating ALDH2 because increased ROS has been found in numerous pathological conditions (i.e., alcoholic and I/R injury), yet antioxidant therapy has not resulted in the expected outcomes clinically.⁷

Beside the documented cardio-protective effects of ALDH2 activity, an exception of the general beneficial role of ALDH2 activity is reported in the aging heart yet, not covered in the current review. Autophagy is an important mechanism for protein quality control in cardiac aging and adaptive remodeling. Global overexpression of ALDH2 in mice led to accentuated suppression of autophagy and a shortened life span. Further evidence suggests that autophagy is regulated by an ALDH2-mediated interaction between Bcl-2, Beclin-1, and the suppression of myocardial autophagy is likely related to the interrupted balance of an ALDH2/JNK1/AMPK signaling pathway. These observations appear to have related epidemiological support in a healthy elderly population, which showed an unexpected positive correlation between cardiac function and the ALDH2*2 genotype (almost no dehydrogenase activity), indicating a complex adaptive cardiac remodeling process occurring with aging in the ALDH2*2 elderly.⁸ However, to fully understand the exact role of ALDH2 in aging and it’s relationships to heart failure and arrhythmia development much effort remains. Finally, an understanding of the epigenetic regulation of ALDH2 is wholly lacking and which could aid in averting the rise in cardiovascular diseases including cardiac arrhythmogenesis associated with lifestyle risk factors.