Characterization of the molecular mechanisms underlying increased ischemic damage in the aldehyde dehydrogenase 2 genetic polymorphism using a human induced pluripotent stem cell model system

Abstract

Nearly 8% of the human population carries an inactivating point mutation in the gene that encodes the cardioprotective enzyme aldehyde dehydrogenase 2 (ALDH2). This genetic polymorphism (ALDH2*2) is linked to more severe outcomes from ischemic heart damage and an increased risk of coronary artery disease (CAD), but the underlying molecular bases are unknown. We investigated the ALDH2*2 mechanisms in a human model system of induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) generated from individuals carrying the most common heterozygous form of the ALDH2*2 genotype. We showed that the ALDH2*2 mutation gave rise to elevated amounts of reactive oxygen species and toxic aldehydes, thereby inducing cell cycle arrest and activation of apoptotic signaling pathways, especially during ischemic injury. We established that ALDH2 controls cell survival decisions by modulating oxidative stress levels and that this regulatory circuitry was dysfunctional in the loss-of-function ALDH2*2 genotype, causing up-regulation of apoptosis in cardiomyocytes after ischemic insult. These results reveal a new function for the metabolic enzyme ALDH2 in modulation of cell survival decisions. Insight into the molecular mechanisms that mediate ALDH2*2-related increased ischemic damage is important for the development of specific diagnostic methods and improved risk management of CAD and may lead to patient-specific cardiac therapies.

Emerging Associations of the ALDH2*2 Polymorphism with Disease Susceptibility

“…Conversely, the ALDH2*2 genotype is thought to be associated with increased apoptosis and myocardial damage during ischemia [1,73]. In an in vitro study, in comparison to wildtype ALDH2*1, heterozygous ALDH2*2/1 tissues were highly sensitive to simulated ischemia in that they displayed significantly elevated levels of ROS and apoptosis [73]. Animal studies also support a role for ALDH2*1 in protection against myocardial ischemia.…”

“…ALDH2 has been shown to oxidize 4-HNE to a less reactive product and is hypothesized to be a protective factor [72]. Conversely, the ALDH2*2 genotype is thought to be associated with increased apoptosis and myocardial damage during ischemia [1,73]. In an in vitro study, in comparison to wildtype ALDH2*1, heterozygous ALDH2*2/1 tissues were highly sensitive to simulated ischemia in that they displayed significantly elevated levels of ROS and apoptosis [73].…”

Induced Pluripotent Stem Cell Model of Pulmonary Arterial Hypertension Reveals Novel Gene Expression and Patient Specificity

“…iPSC can be propagated indefinitely, differentiated into EC and smooth muscle cells (11), and used for vascular disease modeling (12) and drug screening (13), as shown with iPSCderived cardiomyocytes (14,15).…”

Human Induced Pluripotent Stem Cells as a Platform for Personalized and Precision Cardiovascular Medicine

“…Mioulane et al (193) also used the Thermo Scientific Arrayscan imaging platform to study cellular stress induced by chelerythrine, a cell-permeable protein kinase C inhibitor, by performing combined TMRM, caspase-3, and BOBO-1 staining to measure mitochondrial content, apoptosis, and cell death, respectively. More detailed high content assessment of hiPSC-CM mitochondrial function has been performed by measuring glycolysis and oxidative phosphorylation (OXPHOS) using the Seahorse Extracellular Flux Analyzer (63,289).…”