Targeting acid sphingomyelinase reduces cardiac ceramide accumulation in the post-ischemic heart

Abstract

Ceramide accumulation is known to accompany acute myocardial ischemia, but its role in the pathogenesis of ischemic heart disease is unclear. In this study, we aimed to determine how ceramides accumulate in the ischemic heart and to determine if cardiac function following ischemia can be improved by reducing ceramide accumulation. To investigate the association between ceramide accumulation and heart function, we analyzed myocardial left ventricle biopsies from subjects with chronic ischemia and found that ceramide levels were higher in biopsies from subjects with reduced heart function. Ceramides are produced by either de novo synthesis or hydrolysis of sphingomyelin catalyzed by acid and/or neutral sphingomyelinase. We used cultured HL-1 cardiomyocytes to investigate these pathways and showed that acid sphingomyelinase activity rather than neutral sphingomyelinase activity or de novo sphingolipid synthesis was important for hypoxia-induced ceramide accumulation. We also used mice with a partial deficiency in acid sphingomyelinase (Smpd1+/- mice) to investigate if limiting ceramide accumulation under ischemic conditions would have a beneficial effect on heart function and survival. Although we showed that cardiac ceramide accumulation was reduced in Smpd1+/- mice 24 h after an induced myocardial infarction, this reduction was not accompanied by an improvement in heart function or survival. Our findings show that accumulation of cardiac ceramides in the post-ischemic heart is mediated by acid sphingomyelinase. However, targeting ceramide accumulation in the ischemic heart may not be a beneficial treatment strategy.

Association between plasma ceramides and inducible myocardial ischemia in patients with established or suspected coronary artery disease undergoing myocardial perfusion scintigraphy

“…Thus, increased de novo ceramide synthesis might contribute to progressive pathologic cardiac remodeling and dysfunction. To further investigate the association between ceramide accumulation and heart function, Klevstig et al [26] examined myocardial left ventricle biopsies from patients with chronic myocardial ischemia, and found that ceramide levels were higher in biopsies from patients with heart failure. These authors also found that although cardiac ceramide accumulation was reduced 24-hours after an induced myocardial infarction in mice with a partial deficiency in acid sphingomyelinase, this reduction was not accompanied by an improvement in heart function or survival [26].…”

α-Mangostin protects against high-glucose induced apoptosis of human umbilical vein endothelial cells

“…Desipramine is an ASM inhibitor [ 38 ] that can inhibit apoptosis induced by high glucose [ 39 ]. Moreover, the anti-apoptotic action of desipramine is thought to be due to an inhibition of ASM and a reduction in ceramide [ 47 ]. Since α-mangostin has been reported to inhibit ASM activity [ 33 ], it is possible that the anti-apoptotic actions of α-mangostin and desipramine may share similar mechanisms.…”

Cardiovascular Implications of Sphingomyelin Presence in Biological Membranes

“…However, a recent study in mice showed that inhibition of acid SMS does not result in improved heart function or survival after an induced MI despite reducing ischaemia-induced ceramide accumulation. 49 In a rodent model of lipotoxic cardiomyopathy, mice exhibited increased lipid uptake and oxidation, ceramide accumulation and a dilated cardiomyopathy, with decreased functional cardiomyocyte shortening. 49 In contrast, we must emphasise that within this cardiolipotoxic model, ceramides were de novo synthesised within the myocardium and that the mechanism of this cardiac dysfunction was not clear.…”