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. 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 modelailed demonstrations that this association is causative. Unnderstanding 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. the signaling reactions require the HDL receptor, scavenger receptor class B type 1 (SR-B1), an adapter protein (PDZK1) that binds to the cytosolic C terminus of SR-B1, Akt1 activation and (at least in endothelial cells) acti vation of endothelial NO synthase (eNOS). Mouse models of atherosclerosis, 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 atherosclerrosis marketing that HDL signaling may play an important role in protection against coronary artery disease.