Increased de novo ceramide synthesis and accumulation in failing myocardium

Abstract

Abnormal lipid metabolism may contribute to myocardial injury and remodeling. To determine whether accumulation of very long-chain ceramides occurs in human failing myocardium, we analyzed myocardial tissue and serum from patients with severe heart failure (HF) undergoing placement of left ventricular assist devices and controls. Lipidomic analysis revealed increased total and very long-chain ceramides in myocardium and serum of patients with advanced HF. After unloading, these changes showed partial reversibility. Following myocardial infarction (MI), serine palmitoyl transferase (SPT), the rate-limiting enzyme of the de novo pathway of ceramide synthesis, and ceramides were found increased. Blockade of SPT by the specific inhibitor myriocin reduced ceramide accumulation in ischemic cardiomyopathy and decreased C16, C24:1, and C24 ceramides. SPT inhibition also reduced ventricular remodeling, fibrosis, and macrophage content following MI. Further, genetic deletion of the SPTLC2 gene preserved cardiac function following MI. Finally, in vitro studies revealed that changes in ceramide synthesis are linked to hypoxia and inflammation. In conclusion, cardiac ceramides accumulate in the failing myocardium, and increased levels are detectable in circulation. Inhibition of de novo ceramide synthesis reduces cardiac remodeling. Thus, increased de novo ceramide synthesis contributes to progressive pathologic cardiac remodeling and dysfunction.

Adipose tissue ATGL modifies the cardiac lipidome in pressure-overload-induced left ventricular failure

“…Of the 40 detected sphingolipid species in plasma and muscle only 8 correlated significantly [ 51 ]. This is further supported by a recent work from Ji and colleagues investigating the concentration of Cer species in serum and cardiac tissue samples from control and heart failure patients [ 52 ]. From 7 Cer species significantly regulated in serum only 3 exhibited significant changes in myocardial samples [ 52 ].…”

“…This is further supported by a recent work from Ji and colleagues investigating the concentration of Cer species in serum and cardiac tissue samples from control and heart failure patients [ 52 ]. From 7 Cer species significantly regulated in serum only 3 exhibited significant changes in myocardial samples [ 52 ]. Together these data indicate a more complex relationship between tissue and plasma/ serum lipid composition.…”

Sphingolipids in the Heart: From Cradle to Grave

“…Another study in both mice and humans with HF noted increased levels of SPTLC2, which participates in de novo sphingolipid synthesis and likely contributes to the significant increase of total ceramides in the aforementioned studies (45). However, this same study did not note any changes in aSMase or nSMase in HF, the primary catabolic enzymes for ceramide production (45). Therefore, it may be that chronic conditions leading to HF increase de novo synthesis, while acute insults such as MI activate sphingolipid catabolism, though there are clear exceptions to this concept, including nSMase activity was increased 2-3 months post-MI and SPTLC2 was observed to increase 2 weeks post-MI (45,127).…”

“…The nSMase and aSMase hydrolyze sphingomyelin to release ceramide, and thus the accumulation of ceramide in post-ischemic heart may arise from SM catabolism and not de novo sphingolipid biosynthesis (127,128). Another study in both mice and humans with HF noted increased levels of SPTLC2, which participates in de novo sphingolipid synthesis and likely contributes to the significant increase of total ceramides in the aforementioned studies (45). However, this same study did not note any changes in aSMase or nSMase in HF, the primary catabolic enzymes for ceramide production (45).…”

“…These studies established specific roles for subsets of ceramide species and/or CerS enzymes in lipotoxic outcomes in the context of high fat feeding and subsequent diabetes (87,88). Though these studies were conducted in mice and various primary and cultured cardiomyocyte models, the findings may nonetheless bear some relevance to humans (45). Importantly, many of these studies addressed lipotoxicity in the context of metabolic disease; however, other cardiac insults also cause lipotoxicity, and this may proceed by alternative mechanisms (69)(70)(71)(72)(73)(74)(75)(76)89).…”