High-Density Lipoprotein Stimulates Myocardial Perfusion In Vivo

Abstract

Background-Several clinical studies have demonstrated a close association between plasma HDL cholesterol levels and endothelium-dependent vasodilation in peripheral arteries. In isolated arteries, HDL has been shown to mediate vasodilation via NO release. In vivo, administration of reconstituted HDL restored abnormal endothelial function of the brachial artery in hypercholesterolemic patients. However, no data are currently available on the effect of HDL on myocardial perfusion. Methods and Results-In this study, administration of human HDL enhanced incorporation of the perfusion tracer 99m Tc-methoxyisobutylisonitrile ( 99m Tc-MIBI) into the murine heart in vivo by Ϸ18%. This increase was completely abolished in mice deficient for endothelial NO synthase. Because we have recently identified sphingosine 1-phosphate (S1P) as an important vasoactive component contained in HDL, we measured myocardial perfusion after administration of S1P in vivo. We observed an Ϸ25% decrease in myocardial MIBI uptake, which was abolished in mice deficient for the S1P receptor S1P 3 . In S1P 3 Ϫ/Ϫ mice, the stimulatory effect of HDL on myocardial perfusion was preserved. Conclusions-HDL increased myocardial perfusion under basal conditions in vivo via NO-dependent mechanisms, whereas S1P inhibited myocardial perfusion through the S1P 3 receptor. Thus, HDL may reduce coronary risk via direct NO-mediated vasodilatory effects on the coronary circulation. show an inverse relationship between HDL levels and the risk of cardiovascular disease and clinical events. HDL is an independent risk factor in cardiovascular disease, and raising HDL levels alone resulted in a significant risk reduction of major cardiovascular events in patients with coronary disease whose primary lipid abnormality was a low HDL cholesterol level. 1 However, the mechanisms by which HDL exerts its powerful protective effects are still not clear. Among its numerous potential antiatherogenic effects, HDL cholesterol levels are directly associated with flow-mediated vasodilation in clinical patients in vivo, 2 and several experimental studies have shown that HDL directly induces vasodilation through activation of endothelial NO synthase (eNOS) and NO release in isolated arteries ex vivo. 3 Recently, intravenous administration of reconstituted HDL was shown to acutely restore abnormal endothelial function in the brachial artery of hypercholesterolemic patients. 4 In our study we provide evidence that intravenous administration of HDL acutely stimulates myocardial perfusion in vivo in the murine heart via eNOS activation, and we identify the HDL component sphingosine 1-phosphate (S1P) and its receptor S1P 3 as functional opponents of this effect. Methods AnimalsMyocardial perfusion was measured in eNOS-deficient (eNOS Ϫ/Ϫ ) mice (nϭ13; aged 18Ϯ1 weeks; weight, 29.3Ϯ02.4 g) 5 as well as in mice deficient for the lysophospholipid receptor S1P 3 (S1P 3 Ϫ/Ϫ ) (nϭ25; aged 24Ϯ12 weeks; weight, 24.1Ϯ3.6 g) and their wild-type (WT) littermates (nϭ24; aged 24Ϯ11 weeks; weight, 25.2...

Cholesterol binding, efflux, and a PDZ-interacting domain of scavenger receptor–BI mediate HDL-initiated signaling

“…These findings also indicate that minor components of HDL, namely estrogen and sphingosine-1-phosphate (S1P), which have been previously implicated in eNOS activation (35,36), are most likely minimally involved in this pathway. This conclusion is consistent with the observations that HDL activates eNOS in cells devoid of estrogen receptors (14) and that it stimulates myocardial perfusion in mice deficient for the S1P receptor S1P 3 (34). Confirmation of the importance of cholesterol efflux was then obtained in studies of wild-type SR-BI versus the AVI mutant (22), in which the capacity of AVI to mediate efflux to HDL but not to SUVs was paralleled by an ability to signal to eNOS in response to HDL but not to SUV.…”

S1P Signaling and De Novo Biosynthesis in Blood Pressure Homeostasis

“…induced a rapid and transient decrease in heart rate (HR) and MABP in rats (Sugiyama et al, 2000). However, these findings were disputed by others (Bischoff et al, 2000b;Levkau et al, 2004). In a subsequent study, Nofer et al (2004b) confirmed that S1P induced transient hypotension in mice pretreated with ET-1 to raise BP.…”

International Union of Basic and Clinical Pharmacology. LXXVIII. Lysophospholipid Receptor Nomenclature: TABLE 1

“…A clear role for S1P 3 has also been demonstrated in the regulation of heart rate in rodents (Forrest et al, 2004;Sanna et al, 2004), and it has been shown to regulate lymphoid endothelial cells (Girkontaite et al, 2004) and to have effects on endothelial progenitor cells (Walter et al, 2007). S1P 3 regulates myocardial perfusion and provides protection in ischemia-reperfusion injury (Levkau et al, 2004;Theilmeier et al, 2006;Means et al, 2007) and further influences vasorelaxation (Nofer et al, 2004) and cardiac fibrosis (Takuwa et al, 2009). Other influences on myofibroblasts (Keller et al, 2007), as well as S1P 3 links to PAR-1 signaling that couples coagulation events with inflammation (Niessen et al, 2008), have been reported.…”