Is there a genetic basis for resistance to atherosclerosis?
Atherosclerosis and its major clinical manifestation, coronary heart disease, is and will remain the main cause of mortality. Reviews on this subject dealt with factors that enhance development of atherosclerosis. This review deals with a new facet, that some individuals are less prone to develop atherosclerosis: (1) despite high cholesterol intake or (2) despite hypercholesterolemia with elevated low-density lipoprotein cholesterol (LDL-C) levels. The variability of response of plasma cholesterol to dietary intake was shown to be regulated by liver x receptor (LXR) that determines the rate of intestinal cholesterol absorption through the ATP-binding cassette (ABC) gene family. Other gene products, such as apolipoprotein-E (apo-E), scavenger receptor-B1 (SR-B1) and acyl coenzyme: cholesterol acyltransferase-2 (ACAT-2) affect cholesterol absorption also. The role of a genetic background for relative resistance to atherosclerosis is highlighted by subjects with familial hypercholesterolemia in whom high plasma cholesterol levels has not curtailed their expected life span. Studies in animals have shown that resistance to atherosclerosis in spite of hypercholesterolemia is affected by factors such as high-density lipoprotein (HDL) phospholipids that enhance reverse cholesterol transport, non-responsiveness to induction or lack of monocyte chemotactic protein-1 (MCP-1), C-C chemokine receptor 2 (CCR2), macrophage colony stimulating factor (MCSF), or vascular cell adhesion molecule-1 (VCAM-1). Since macrophages have been regarded as pro- or anti-atherogenic, evidence was collated that the high activity of scavenger receptors may contribute towards resistance to atherosclerosis if accompanied by adequate amounts of apo-E for cholesterol removal.
Stein
Olga
O
Department of Experimental Medicine and Cancer Research, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Thiery
Joachim
J
Stein
Yechezkiel
Y
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D001161:Arteriosclerosis / Q000150:complications / Q000235:genetics*; D018955:CD36 Antigens / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D018932:Chemokine CCL2 / Q000235:genetics; D002784:Cholesterol / Q000097:blood / Q000235:genetics; D002791:Cholesterol, Dietary; D003327:Coronary Disease / Q000150:complications / Q000235:genetics; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D006937:Hypercholesterolemia / Q000150:complications / Q000235:genetics; D000071518:Liver X Receptors; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics; D008565:Membrane Proteins; D057093:Orphan Nuclear Receptors; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D018168:Receptors, Retinoic Acid / Q000235:genetics; D051116:Receptors, Scavenger; D011988:Receptors, Thyroid Hormone / Q000235:genetics; D051122:Scavenger Receptors, Class B; D002785:Sterol O-Acyltransferase / Q000235:genetics; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics; D014655:Vascular Resistance / Q000235:genetics*
C108069:ATP-binding protein, liver; D001057:Apolipoproteins E; C515334:CCR2 protein, human; D018955:CD36 Antigens; D002352:Carrier Proteins; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D002791:Cholesterol, Dietary; D004268:DNA-Binding Proteins; D005819:Genetic Markers; D000071518:Liver X Receptors; D008565:Membrane Proteins; D057093:Orphan Nuclear Receptors; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D018160:Receptors, Cytoplasmic and Nuclear; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D018168:Receptors, Retinoic Acid; D051116:Receptors, Scavenger; D011988:Receptors, Thyroid Hormone; C495124:SCARB1 protein, human; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D019010:Vascular Cell Adhesion Molecule-1; D016173:Macrophage Colony-Stimulating Factor; D002784:Cholesterol; D002785:Sterol O-Acyltransferase