Impaired Cardioprotection by HDL in CAD and Diabetes in Ischemia/Reperfusion Injury: role of S1P and SR-BI

Abstract Background HDL dysfunction rather than HDL-cholesterol concentration is involved in the pathogenesis of coronary artery disease (CAD) and type-2 diabetes (T2DM). While causes consequences are manifold, reduced concentrations HDL-sphingosine-1-phsophate (S1P) partially responsible for impaired vasodilation suppression inflammation by CAD-HDL. Administration healthy human prior to ischemia/reperfusion (I/R) mice infarct size (IS) due HDL-S1P. The role major receptor SR-BI unexplored this context. Purpose In study, we, a) investigated cardioprotective properties versus CAD-HDL T2DM-HDL a murine model acute myocardial infarction (AMI), b) tested effect S1P loading cardioprotection, c) detected relevant cardioprotection. Methods were isolated from plasma volunteers, CAD, T2DM patients density ultra-centrifugation injected (43 mg protein/KG) tail vein C57Bl/6J 5 minutes 30 ischemia. Cardiac function was assessed after 24 hours reperfusion echocardiography. IS analyzed TTC staining measured LC-MS/MS, respectively. Results 23% increased ejection fraction (EF) 22% I/R (IS: Control 43.8±6.9% [n=17] vs. 32.9±3.6% [n=9]; EF: 34.5±5.7% 41.9±4.1%). contrast, same dosage had no protective 40.1±5.7% [n=12]; 31.9±8.4%). As HDL-S1P 33% lower compared HDL, we whether S1P-loading may correct CAD-HDL's defective Indeed, (38 μg S1P/kg 43 completely restored cardioprotection levels achieved HDL. additional benefit. led 28% larger worse EF 33.0±4.3% [n=6] 42.4±8.9% [n=13]; 38.5±5.8% 33.1±.4.0%). Compared exhibited 19% decrease content. We thus mediated using global deficient (Scarb1−/−). Remarkably, administration absent Scarb1−/− but intact wild type controls. (IS Scarb1++: Vehicle 38.6±8.3% [n=12] 29.9±8.5% [n=11], Scarb1−/−: 31.4±5.6% 31.1±6.9% [n=17]) Conclusion have identified: (a) as new characteristic CAD T2DM; (b) low its cause possibility therapeutic correction loading, (c) HDL-S1P-mediated Funding Acknowledgement Type funding sources: None.