Abstract Body: The heart primarily relies on long chain fatty acid oxidation (LCFA) to meet ATP demand. CD36, is a transmembrane glycoprotein transferase for LCFA uptake widely expressed in several cell types including endothelial cells (ECs), cardiomyocytes (CMs), skeletal myocytes, adipocytes, and monocyte/macrophages. Notably, genetic deficiency of CD36 in humans is associated with hypertrophic cardiomyopathy. The role of CD36 in transendothelial LCFA delivery to CMs under physiologic vs pathologic conditions is unknown. We explored consequences of EC-specific CD36 deletion (EC-CD36 KO mice) on the cardiac response to pressure overload.
Lack of EC-CD36 increased severity of left ventricular hypertrophy (LVH), and systolic and diastolic dysfunction at 8 weeks of pressure overload via transverse aortic constriction (TAC), with increases in HW:TL ratio, LV mass by echo, reduced EF (p<0.05), and elevated E/E’ in EC-CD36-KO vs. flox/flox littermate controls (f/f) (p<0.5) (Fig 1). Dynamic mode ¹³C NMR revealed delayed ¹³C LCFA uptake kinetics (time constant, τ) in CMs of isolated, sham and TAC EC-CD36 KO hearts provided ¹³C palmitate + ¹³C oleate (0.02 mM each) + 10 mM glucose + 1 mM lactate (Fig 2). ¹³C LCFA esterification into triglyceride (TG) was also reduced in EC-CD36-KO vs f/f controls, but without evidence for an additional effect of TAC.
The contribution of ¹³C LCFA to acetyl CoA entry into oxidation via the TCA cycle, was reduced by lack of EC-CD36 in sham and TAC hearts (p<0.0001) (Fig 2). Consistent with diminished LCFA oxidation, phosphocreatine (PCr) to ATP ratio was also compromised in EC-CD36-KO-TAC hearts (p<0.05). Lack of EC-CD36 during TAC increased ¹³C LCFA trafficking to lipotoxic C16 ceramide in EC-CD36 KO hearts (Fig 3).
CD36 in ECs is critical to LCFA delivery to CMs during pathological stress on the heart. The imbalance in intramyocellular LCFA dynamics due to restricted transendothelial delivery of LCFA to CMs increased lipotoxic ceramide formation. Thus, EC CD36 is critical to the adaptive cardiac response to pathological stress, and the absence of EC CD36-dependent delivery of LCFA to CMs exacerbates reduced energy potential, adverse cardiac remodeling, and dysfunction during afterload stress.