HDL signaling and protection against coronary artery atherosclerosis in mice

Abstract

Atherosclerosis is a leading underlying factor in cardiovascular disease and stroke, important causes of morbidity and mortality across the globe. Abundant epidemiological studies demonstrate that high levels of high density lipoprotein (HDL) are associated with reduced risk of atherosclerosis and preclinical, animal model studies demonstrate that this association is causative. Understanding the molecular mechanisms underlying the protective effects of HDL will allow more strategic approaches to development of HDL based therapeutics. Recent evidence suggests that an important aspect of the ability of HDL to protect against atherosclerosis is its ability to trigger signaling responses in a variety of target cells including endothelial cells and macrophages in the vessel wall. These signaling responses require the HDL receptor, scavenger receptor class B type 1 (SR-B1), an adaptor protein (PDZK1) that binds to the cytosolic C terminus of SR-B1, Akt1 activation and (at least in endothelial cells) activation of endothelial NO synthase (eNOS). Mouse models of atherosclerosis, exemplified by apolipoprotein E or low density lipoprotein receptor gene inactivated mice (apoE or LDLR KO) develop atherosclerosis in their aortas but appear generally resistant to coronary artery atherosclerosis. On the other hand, inactivation of each of the components of HDL signaling (above) in either apoE or LDLR KO mice renders them susceptible to extensive coronary artery atherosclerosis suggesting that HDL signaling may play an important role in protection against coronary artery disease.

Keywords: coronary artery disease; high density lipoprotein; myocardial infarction; scavenger receptor class B type 1.

Fig. 1. HDL signaling via SR-B1 and role in coronary artery atherosclerosis.

HDL signaling via SR-B1 involves PDZK1 (shown binding to the C-terminal tail of SR-B1 via one of the two possible PDZ domains known to bind there), activation of Akt1 and eNOS. Germline whole body knockout of SR-B1, PDZK1, Akt1 and eNOS (red boxes) on atherogenic ApoE or LDLR KO backgrounds have all been shown to trigger either spontaneous (SR-B1/apoE) or diet induced coronary artery atherosclerosis and myocardial infarction (PDZK1, Akt1 or eNOS on apoE KO; SR-BI on apoE-hypo or LDLR KO backgrounds)^{[19,21,23,31-33]}. More detailed descriptions of HDL signaling pathways mediated by SR-B1 can be found in references^[8-9].

Fig. 2. Occlusive coronary artery atherosclerosis in an atherogenic diet fed SR-B1/LDLR double KO mouse:

In an experiment described in⁽²³⁾, an SR-B1/LDLR double KO mouse was fed the Paigen atherogenic diet for 3.5 weeks. Shown is a series of cross sections through the same coronary artery (passing through the septum of the heart), just below (A) and (B) and at (C) a bifurcation. (A) Oil red O (lipid-red)/hematoxylin (nuclei-blue) stained section. (B) Immunofluorescence staining for CD41 (platelet-red); counterstained with DAPI (nuclei-blue). Green: autofluorescence. Arrow points to red CD41 staining. (C) Trichrome staining. Fibrous tissue appears blue. Scale bar = 30 μm.