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HDL signaling and protection against coronary artery atherosclerosis in mice
Bernardo L Trigatti1, Mark Fuller2
1Department of Biochemistry and Biomedical Sciences, McMaster University and Thrombosis and Atherosclerosis Research Institute, McMaster University and Hamilton Health Sciences., Hamilton, Ontario L8L 2X2, Canada; trigatt@mcmaster.ca.
Insights
High-density lipoprotein (HDL) protects against atherosclerosis by triggering cell signaling pathways. Disrupting these pathways, involving scavenger receptor class B type 1 (SR-B1), increases coronary artery disease risk.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Cell Signaling
Background:
- Atherosclerosis is a major global cause of death, linked to cardiovascular disease and stroke.
- High levels of high-density lipoprotein (HDL) are epidemiologically associated with reduced atherosclerosis risk.
- Understanding HDL's protective mechanisms is crucial for developing targeted therapies.
Purpose of the Study:
- To elucidate the molecular mechanisms by which HDL protects against atherosclerosis.
- To investigate the role of HDL-mediated cell signaling in preventing coronary artery disease.
Main Methods:
- Examined HDL's ability to trigger signaling responses in endothelial cells and macrophages.
- Investigated the involvement of scavenger receptor class B type 1 (SR-B1), PDZK1, Akt1, and endothelial NO synthase (eNOS) in HDL signaling.
- Utilized apolipoprotein E (apoE) or low-density lipoprotein receptor (LDLR) knockout mouse models.
Main Results:
- HDL signaling, dependent on SR-B1, PDZK1, Akt1, and eNOS, plays a key role in protecting against atherosclerosis.
- Inactivation of HDL signaling components in apoE or LDLR knockout mice led to susceptibility to coronary artery atherosclerosis.
- HDL signaling appears critical for preventing coronary artery disease.
Conclusions:
- HDL exerts protective effects against atherosclerosis through specific cell signaling pathways.
- Targeting HDL-mediated signaling pathways offers a potential therapeutic strategy for cardiovascular disease.
- HDL signaling is vital in preventing coronary artery atherosclerosis.
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.
