Abstract
SR-BI deficient mice that are also hypomorphic for apolipoprotein E expression develop diet induced occlusive coronary artery atherosclerosis, myocardial infarction and early death. To test the role of SR-BI in bone marrow derived cells, we used bone marrow transplantation to generate SR-BI-null; apoE-hypomorphic mice in which SR-BI expression was restored solely in bone marrow derived cells. SR-BI-null; apoE-hypomorphic mice were transplanted with SR-BI+/+apoE-hypomorphic, or control, autologous SR-BI-null; apoE-hypomorphic bone marrow. Four weeks later, mice were fed a high-fat, high-cholesterol, cholate-containing diet to induce coronary artery atherosclerosis. Mice transplanted with autologous bone marrow developed extensive aortic atherosclerosis and severe occlusive coronary artery atherosclerosis after 4 weeks of feeding. This was accompanied by myocardial fibrosis and increased heart weights. In contrast, restoration of SR-BI expression in bone marrow derived-cells reduced diet induced aortic and coronary artery atherosclerosis, myocardial fibrosis and the increase in heart weights in SR-BI-null; apoE-hypomorphic mice. Restoration of SR-BI in bone marrow derived cells did not, however, affect steady state lipoprotein cholesterol levels, but did reduce plasma levels of IL-6. Monocytes from SR-BI-null mice exhibited a greater capacity to bind to VCAM-1 and ICAM-1 than those from SR-BI+/+ mice. Furthermore, restoration of SR-BI expression in bone marrow derived cells attenuated monocyte recruitment into atherosclerotic plaques in mice fed high fat, high cholesterol cholate containing diet. These data demonstrate directly that SR-BI in bone marrow-derived cells protects against both aortic and CA atherosclerosis.
Highlights
The scavenger receptor class B type I (SR-BI) is a multiligand receptor that binds to high density lipoprotein (HDL) with high affinity and mediates the selective uptake of HDL lipids [1], cellular cholesterol efflux from cells [2] and HDL dependent signaling [3]
We demonstrate that restoration of normal SR-BI expression in bone marrow (BM)-derived cells protected against diet induced aortic and coronary artery (CA) atherosclerosis, myocardial infarction and increases in heart weights in SR-BI2/2apoE-hypomorphic mice, without substantially affecting plasma or lipoprotein cholesterol levels
SR-BI2/2apoE2/2 mice develop spontaneous and SR-BI2/2 apoE-hypomorphic mice develop high fat, high cholesterol dietinduced accelerated aortic sinus and occlusive coronary artery atherosclerosis that is accompanied by cardiac fibrosis and enlargement, cardiac conductance and function abnormalities and early death within weeks [10,14,21,22,23]
Summary
The scavenger receptor class B type I (SR-BI) is a multiligand receptor that binds to high density lipoprotein (HDL) with high affinity and mediates the selective uptake of HDL lipids [1], cellular cholesterol efflux from cells [2] and HDL dependent signaling [3]. SR-BI knockout (KO) mice exhibit defective HDLdependent reverse cholesterol transport from macrophages, resulting in increased plasma HDL-associated cholesterol and reduced cholesterol in bile [4,5,6,7,8,9]. Overexpression of SR-BI in livers of mice has the opposite effects, reducing both HDL cholesterol levels and atherosclerosis [15,16,17,18,19,20]. SR-BI/apoE double KO mice rapidly (within 6 weeks of age) develop occlusive coronary artery (CA) atherosclerosis and exhibit extensive myocardial fibrosis, ECG abnormalities, cardiac enlargement, reduced heart function (ejection fraction, contractility and relaxation) and early death [10,21,22,23].
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