Hypercholesterolemia Promotes a CD36-dependent and Endothelial Nitric-oxide Synthase-mediated Vascular Dysfunction

Abstract

Numerous studies have implicated either the presence or absence of CD36 in the development of hypertension. In addition, hypercholesterolemia is associated with the loss of nitric oxide-induced vasodilation and the subsequent increase in blood pressure. In the current study, we tested the hypothesis that diet-induced hypercholesterolemia promotes the disruption of agonist-stimulated nitric oxide generation and vasodilation in a CD36-dependent manner. To test this, C57BL/6, apoE null, CD36 null, and apoE/CD36 null mice were maintained on chow or high fat diets. In contrast to apoE null mice fed a chow diet, apoE null mice fed a high fat diet did not respond to acetylcholine with a decrease in blood pressure. Caveolae isolated from in vivo vessels did not contain endothelial nitric-oxide synthase and were depleted of cholesterol. Age-matched apoE/CD36 null mice fed a chow or high fat diet responded to acetylcholine with a decrease in blood pressure. The mechanism underlying the vascular dysfunction was reversible because vessels isolated from apoE null high fat-fed mice regained responsiveness to acetylcholine when incubated with plasma obtained from chow-fed mice. Further analysis demonstrated that the plasma low density lipoprotein fraction was responsible for depleting caveolae of cholesterol, removing endothelial nitric-oxide synthase from caveolae, and preventing nitric oxide production. In addition, the pharmacological removal of caveola cholesterol with cyclodextrin mimicked the effects caused by the low density lipoprotein fraction. We conclude that the ablation of CD36 prevented the negative impact of hypercholesterolemia on agonist-stimulated nitric oxide-mediated vasodilation in apoE null mice. These studies provide a direct link between CD36 and the early events that underlie hypercholesterolemia-mediated hypertension and mechanistic linkages between CD36 function, nitric-oxide synthase activation, caveolae integrity, and blood pressure regulation.CD36 is a class B scavenger receptor that is expressed in cardiac myocytes, adipocytes, macrophages, platelets, and microvascular endothelial cells (1, 2). Recent studies with mice and rats that lack CD36 demonstrate a role for this protein in atherosclerosis (3), angiogenesis (4), and diabetes (5-7). Genetic linkage studies implicate the absence of CD36 in the development of hypertension (8), although direct experimental evidence is lacking. One of the confounding factors in the linkage studies is that genes involved in blood pressure regulation such as endothelial nitric-oxide synthase, leptin, and neuropeptide Y are linked to CD36 within chromosome 4, making it difficult to attribute changes in blood pressure to CD36 (8, 9). Studies by Pravenec et al. (8) demonstrate that the transfer of a segment of chromosome 4 to spontaneous hypertensive rats (lack CD36) normalized blood pressure; however, when just CD36 was transferred, blood pressure did not normalize (10). In contrast, Greenwalt et al. (11) demonstrate that CD36 was increased in animal hypertensive...

CD36: Implications in cardiovascular disease

“…In some cell types, expression of caveolin-1 has been shown to be necessary for plasma membrane targeting of CD36, and disruption of caveolae may effect some CD36 dependent functions (Ring, Le Lay, Pohl, Verkade, & Stremmel 2006,Vistisen, Roepstorff, Roepstorff, Bonen, van Deurs, & Kiens, 2004,Frank, Lee, Park, Tandon, Scherer, & Lisanti,. 2004,Pohl, Ring, Korkmaz, Ehehalt, & Stremmel, 2005,Kincer, et al, 2002, Dorahy, Lincz, Meldrum, & Burns, 1996. The partitioning of CD36 to specific plasma membrane domains may facilitate interaction with signaling partners that are essential to CD36 dependent responses.…”

Reduction of Blood Pressure, Plasma Cholesterol, and Atherosclerosis by Elevated Endothelial Nitric Oxide

“…2). Recently it was shown that hypercholesterolemia in mice results in CD36-mediated cholesterol depletion of caveolae, followed by translocation of eNOS from caveolae and subsequent inactivation of the enzyme (42). Thus, eNOS activity is directly related to the cholesterol content of caveolae.…”

Caveolin, Caveolae, and Endothelial Cell Function

“…This observation might be the result of disruption of the signal transduction complex containing eNOS, caveolin-1, and other molecules required for eNOS activation. Recent work by Kincer et al 58 has shown that CD36, a class B scavenger receptor associated with caveolae, was probably responsible for this effect. 58 This observation is important in view of the fact that in hypercholesterolemic patients or animal models, impairment of endothelium-derived relaxation is observed.…”

“…Recent work by Kincer et al 58 has shown that CD36, a class B scavenger receptor associated with caveolae, was probably responsible for this effect. 58 This observation is important in view of the fact that in hypercholesterolemic patients or animal models, impairment of endothelium-derived relaxation is observed. 59 -61 In agreement with this finding, Feron et al 62 have shown that exposure of endothelial cells to serum from hypercholesterolemic patients promotes an increase in the caveolin-1-eNOS interaction.…”