Abstract 353: Genetic Mutation of ALDH2 Enhances Cardiomyocyte Tolerance to Oxidative Stress as a Result of Hormetic Response to Aldehydes
[Introduction]Aldehyde dehydrogenases (ALDH) play a major role in the detoxification of aldehydes produced by lipid peroxidation under oxidative stress. The single nucleotide polymorphism of ALDH2 (ALDH2*2), which is found in Asian and works as a dominant negative, is not only associated with alcohol flushing syndrome, but also is a risk for senescence-associated diseases, such as Alzheimer’s disease, cardiovascular diseases, and cancers. This study was designed to investigate the alteration of cardiac peroxidized lipid metabolism in response to the genetic mutation of ALDH2.
[Methods and Results]
Transgenic (Tg) mice harboring ALDH2*2 exhibited the phenocopy of senescence including muscle atrophy, diminished fat, osteopenia, and kyphosis during development to reproductive maturity.
These mice revealed the profound mitochondrial architecture abnormalities in cardiac muscles. Nevertheless, neither contractile dysfunction nor cellular degeneration and death emerged.
Furthermore, they acquired resistance to oxidative stress. We characterized the alteration of the metabolic pathway occurring in ALDH2*2 Tg hearts by integrated transcriptomic and metabolomic analyses.
The levels of reduced glutathione (GSH) was increased, which closely corresponds to the expression of a set of enzymes involved in biosynthesis of glutathione and to the redirection of glycolytic flux towards the pentose phosphate pathway to produce NADPH.
Lipidomics analysis of oxidized lipids in the hearts by LC-MS/MS revealed an enhanced reduction of both phospholipids and fatty acid form of linoleic acid hydroperoxides and a resultant accumulation of hydroxyoctadecanoic acids in ALDH2*2 Tg mice.
In cultured cardiomyocytes, both the treatment of low dose of 4-hydroxynonenal and adenovirus-mediated expression of ALDH2*2 protects cardiomyocytes against subsequent oxidative stress via up-regulating the expression of genes involved in GSH biosynthesis as seen in ALDH2*2 Tg hearts.
[Conclusions]Genetic mutation of ALDH2 induces an increased flux towards intracellular GSH biosynthesis and an enhanced ability to eliminate lipid hydroperoxide. This hormetic response to aldehydes enhanced cardiomyocyte tolerance to oxidative stress.