Presentation description

BACKGROUND: Heart failure (HF) remains the leading cause of death in the United States. To meet high metabolic demands, the healthy heart primarily breaks down fatty acids for energy. However, in HF, fatty acid oxidation and breakdown of toxic lipids such as sphingolipids (SGLs) decline. Accumulation of SGLs like ceramides (Cer) in cardiomyocytes has been linked to HF in humans and animal models. Cer can be degraded through several pathways, including one mediated by UDP-glucose ceramide glucosyltransferase (UGCG), which converts Cer into glucosylceramides (GlcCer).

PURPOSE: This study aims to further investigate and understand the role Cer and UGCG play in HF development.

METHODS: This study investigates the role of Cer and UGCG in HF progression using an inducible, cardiac-specific UGCG knockout mouse model (UGCGicKO). Serial echocardiography assessed cardiac function and structure. Heart tissue was collected at 8- and 24-weeks post-injection (WPI). Cardiomyocytes were isolated via Langendorff perfusion. Transcriptomic and lipidomic analyses were conducted on heart tissue and serum from UGCGicKO and wild-type (WT) mice.

RESULTS: At 8 WPI, UGCG mRNA expression was significantly reduced in UGCGicKO cardiomyocytes. By 24 WPI, UGCGicKO mice showed decreased ejection fraction and fractional shortening, with altered ventricular wall/body weight ratios compared to WT. Lipidomic profiling revealed elevated Cer(22:0) levels and decreased GlcCer(16:0, 22:0, 24:0, 24:1) in UGCGicKO hearts at 24 WPI compared to UGCGicKO at 8 WPI and WT.

CONCLUSIONS: Our findings identify UGCG as a key regulator of cardiac metabolic homeostasis in HF, offering potential therapeutic targets for reversing metabolic remodeling in HF. Further studies are needed to identify the downstream mechanisms behind the role of UGCG and GlcCer in HF.