Rationale: Lipid overload-induced heart dysfunction is characterized by cardiomyocyte death, myocardial remodeling, and compromised contractility, but the impact of excessive lipid supply on cardiac function remains poorly understood. Objective: To investigate the regulation and function of the mitochondrial fission protein Drp1 (dynamin-related protein 1) in lipid overload-induced cardiomyocyte death and heart dysfunction. Methods and Results: Mice fed a high-fat diet (HFD) developed signs of obesity and type II diabetes mellitus, including hyperlipidemia, hyperglycemia, hyperinsulinemia, and hypertension. HFD for 18 weeks also induced heart hypertrophy, fibrosis, myocardial insulin resistance, and cardiomyocyte death. HFD stimulated mitochondrial fission in mouse hearts. Furthermore, HFD increased the protein level, phosphorylation (at the activating serine 616 sites), oligomerization, mitochondrial translocation, and GTPase activity of Drp1 in mouse hearts, indicating that Drp1 was activated. Monkeys fed a diet high in fat and cholesterol for 2.5 years also exhibited myocardial damage and Drp1 activation in the heart. Interestingly, HFD decreased nicotinamide adenine dinucleotide (oxidized) levels and increased Drp1 acetylation in the heart. In adult cardiomyocytes, palmitate increased Drp1 acetylation, phosphorylation, and protein levels, and these increases were abolished by restoration of the decreased nicotinamide adenine dinucleotide (oxidized) level. Proteomics analysis and in vitro screening revealed that Drp1 acetylation at lysine 642 (K642) was increased by HFD in mouse hearts and by palmitate incubation in cardiomyocytes. The nonacetylated Drp1 mutation (K642R) attenuated palmitate-induced Drp1 activation, its interaction with voltage-dependent anion channel 1, mitochondrial fission, contractile dysfunction, and cardiomyocyte death. Conclusions: These findings uncover a novel mechanism that contributes to lipid overload-induced heart hypertrophy and dysfunction. Excessive lipid supply created an intracellular environment that facilitated Drp1 acetylation, which, in turn, increased its activity and mitochondrial translocation, resulting in cardiomyocyte dysfunction and death. Thus, Drp1 may be a critical mediator of lipid overload-induced heart dysfunction as well as a potential target for therapy.

Hydrogen sulfide (H₂S) and nitric oxide (NO) are now recognized as important regulators in the cardiovascular system, although they were historically considered as toxic gases. As gaseous transmitters, H₂S and NO share a wide range of physical properties and physiological functions: they penetrate into the membrane freely; they are endogenously produced by special enzymes, they stimulate endothelial cell angiogenesis, they regulate vascular tone, they protect against heart injury, and they regulate target protein activity via posttranslational modification. Growing evidence has determined that these two gases are not independent regulators but have substantial overlapping pathophysiological functions and signaling transduction pathways. H₂S and NO not only affect each other’s biosynthesis but also produce novel species through chemical interaction. They play a regulatory role in the cardiovascular system involving similar signaling mechanisms or molecular targets. However, the natural precise mechanism of the interactions between H₂S and NO remains unclear. In this review, we discuss the current understanding of individual and interactive regulatory functions of H₂S and NO in biosynthesis, angiogenesis, vascular one, cardioprotection, and posttranslational modification, indicating the importance of their cross‐talk in the cardiovascular system.