Mitochondrial aldehyde dehydrogenase and cardiac diseases

Abstract

Numerous conditions promote oxidative stress, leading to the build-up of reactive aldehydes that cause cell damage and contribute to cardiac diseases. Aldehyde dehydrogenases (ALDHs) are important enzymes that eliminate toxic aldehydes by catalysing their oxidation to non-reactive acids. The review will discuss evidence indicating a role for a specific ALDH enzyme, the mitochondrial ALDH2, in combating oxidative stress by reducing the cellular 'aldehydic load'. Epidemiological studies in humans carrying an inactive ALDH2, genetic models in mice with altered ALDH2 levels, and small molecule activators of ALDH2 all highlight the role of ALDH2 in cardioprotection and suggest a promising new direction in cardiovascular research and the development of new treatments for cardiovascular diseases.

Figure 1

A scheme depicting aldehyde-induced mitochondrial damage and how ALDH2 reduces this aldehydic toxicity. (Left) Ischaemia and reperfusion and other oxidative stress in the heart increase ROS production, which triggers lipid peroxidation and the accumulation of reactive aldehydes, such as 4-HNE. Other xenogenic aldehydes from the environment, from ethanol metabolism, and from food additives can also increase the cellular ‘aldehydic load’ (depicted as a grey cloud in the figure). Aldehydes induce inactivation of a number of macromolecules including the proteasome, the electron transport chain (ETC) in the mitochondria, as well as inactivation of ALDH2 itself. This aldehyde-induced macromolecule inactivation contributes to mitochondrial impairment and increases in oxidative stress, thus leading to cell damage. Particularly relevant to cardiac disease, the use of nitroglycerin (GTN) can further contribute to ALDH2 inactivation, thus decreasing the cell's natural ability to reduce ROS-induced aldehydic load and cytotoxicity. Finally, a common mutation in ALDH2 (ALDH2*2) in humans further impairs the ability to reduce the aldehydic load under oxidative stress conditions. (Right) Agents that increase ALDH2 activity and protect ALDH2 from inactivation by aldehydes and by GTN will decrease the aldehydic load by enhancing the conversion of aldehydes to non-reactive acid (blue cloud in the scheme), thus leading to cytoprotection. Such one potential agent is Alda-1, an aldehyde dehydrogenase 2 activator. Alda-1 increases ALDH2 activity by about two-folds, blocks ALDH2 inactivation by both aldehydes and GTN, and thus increases the cell's natural ability to protect from oxidative stress, leading to 60% reduction from cardiac damage in an animal model of AMI. The ability of Alda 1 to increase the activity of the mutant ALDH2*2 may be of particular importance for over >0.5 billion humans who carry this mutation. (See text for details.) Reduction in aldehydic load decreases mitochondrial structural and functional damages and increases ATP generation, thus leading to cardiac protection from oxidative stress.