Regulation and therapeutic strategies of 4-hydroxy-2-nonenal metabolism in heart disease

4-hydroxy-2-nonenal (4- HNE), a reactive aldehyde, is generated from polyunsaturated fatty acids (PUFAs) in biological membranes. Reactive oxygen species (ROS) generated during oxidative stress react with PUFAs to form aldehydes like 4- HNE, which inactivates proteins and DNA by forming hybrid covalent chemical addition compounds called adducts. The ensuing chain reaction results in cellular dysfunction and tissue damage. It includes a wide spectrum of events ranging from electron transport chain dysfunction to apoptosis. In addition, 4- HNE directly depresses contractile function, enhances ROS formation, modulates cell signaling pathways, and can contribute to many cardiovascular diseases, including atherosclerosis, myocardial ischemia - reperfusion injury, heart failure, and cardiomyopathy. Therefore, targeting 4- HNE could help reverse these pathologies. This review will focus on 4- HNE generation, the role of 4- HNE in cardiovascular diseases, cellular targets (especially mitochondria), processes and mechanisms for 4- HNE-induced toxicity, regulation of 4- HNE metabolism, and finally strategies for developing potential therapies for cardiovascular disease by attenuating 4- HNEinduced toxicity.