Improving Reconstituted HDL Composition for Efficient Post-Ischemic Reduction of Ischemia Reperfusion Injury

Abstract

BackgroundNew evidence shows that high density lipoproteins (HDL) have protective effects beyond their role in reverse cholesterol transport. Reconstituted HDL (rHDL) offer an attractive means of clinically exploiting these novel effects including cardioprotection against ischemia reperfusion injury (IRI). However, basic rHDL composition is limited to apolipoprotein AI (apoAI) and phospholipids; addition of bioactive compound may enhance its beneficial effects.ObjectiveThe aim of this study was to investigate the role of rHDL in post-ischemic model, and to analyze the potential impact of sphingosine-1-phosphate (S1P) in rHDL formulations.Methods and ResultsThe impact of HDL on IRI was investigated using complementary in vivo, ex vivo and in vitro IRI models. Acute post-ischemic treatment with native HDL significantly reduced infarct size and cell death in the ex vivo, isolated heart (Langendorff) model and the in vivo model (-48%, p<0.01). Treatment with rHDL of basic formulation (apoAI + phospholipids) had a non-significant impact on cell death in vitro and on the infarct size ex vivo and in vivo. In contrast, rHDL containing S1P had a highly significant, protective influence ex vivo, and in vivo (-50%, p<0.01). This impact was comparable with the effects observed with native HDL. Pro-survival signaling proteins, Akt, STAT3 and ERK1/2 were similarly activated by HDL and rHDL containing S1P both in vitro (isolated cardiomyocytes) and in vivo.ConclusionHDL afford protection against IRI in a clinically relevant model (post-ischemia). rHDL is significantly protective if supplemented with S1P. The protective impact of HDL appears to target directly the cardiomyocyte.

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

“…For example, HDL-associated S1P appears to be important for the vasoprotective effects on endothelial cell survival, 104 109 and nitric oxide-dependent vasorelaxation. 20 It also inhibits vascular smooth muscle cell migration and chemokine production, 31, 110 cardiomyocyte apoptosis during hypoxia-reoxygenation, 111,112 and myocardial damage after ischemia/reperfusion. 112,113 Of note, at least some functions of S1P appear to be only exerted if S1P is present on HDL.…”

“…20 It also inhibits vascular smooth muscle cell migration and chemokine production, 31, 110 cardiomyocyte apoptosis during hypoxia-reoxygenation, 111,112 and myocardial damage after ischemia/reperfusion. 112,113 Of note, at least some functions of S1P appear to be only exerted if S1P is present on HDL. 107 This is of note because only about 50% of S1P in plasma is transported by HDL.…”

Understanding STAT3 signaling in cardiac ischemia

“…Cardiac inflammation resulting from MI leads to increased secretion of pro-inflammatory cytokines such as IL-1b, IL-6, and TNF-a, which leucocytes to the infarcted area in an inflammatory response designed to help the myocardium to recover from the ischaemic insult [10]. This can also be detrimental if prolonged beyond the acute phase.…”

Implication of sphingosin-1-phosphate in cardiovascular regulation

“…In addition, in a mouse model of ischemia/reperfusion, post-conditioning with S1P significantly reduces the infarct size and improves cardiac function, which is shown to be S1P3 receptor-dependent, as the protective effect of S1P is absent in S1P3 knockout mice (69). Moreover, reconstituted (synthetic) HDL (rHDL) that is artificially added with S1P significantly potentiates the cardioprotective effect of rHDL and that the protective effect of rHDL appears to target directly the cardiomyocyte (70). S1P signaling is also shown to mediate the cardioprotective effect of adiponectin, as an antagonist of S1P1/3 abolishes the protective effect of adiponectin against the ischemia/reperfusion injury in mouse heart in vivo (71).…”