Cathepsin G deficiency decreases complexity of atherosclerotic lesions in apolipoprotein E-deficient mice.
Cathepsin G is a serine protease with a broad range of catalytic activities, including production of angiotensin II, degradation of extracellular matrix and cell-cell junctions, modulation of chemotactic responses, and induction of apoptosis. Cathepsin G mRNA expression is increased in human coronary atheroma vs. the normal vessel. To assess whether cathepsin G modulates atherosclerosis, cathepsin G knockout (Cstg(-/-)) mice were bred with apolipoprotein E knockout (Apoe(-/-)) mice to obtain Ctsg(+/-)Apoe(-/-) and Ctsg(+/+)Apoe(-/-) mice. Heterozygous cathepsin G deficiency led to a 70% decrease in cathepsin G activity in bone marrow cells, but this reduced activity did not impair generation of angiotensin II in bone marrow-derived macrophages (BMDM). Atherosclerotic lesions were compared in male Cstg(+/-)Apoe(-/-) and Cstg(+/+)Apoe(-/-) mice after 8 wk on a high-fat diet. Plasma cholesterol levels and cholesterol distribution within serum lipoprotein fractions did not differ between genotypes nor did the atherosclerotic lesion areas in either the aortic root or aortic arch. Cstg(+/-)Apoe(-/-) mice, however, showed a lower percentage of complex lesions within the aortic root and a smaller number of apoptotic cells compared with Cstg(+/+)Apoe(-/-) littermates. Furthermore, apoptotic Cstg(-/-) BMDM were more efficiently engulfed by phagocytic BMDM than were apoptotic Ctsg(+/+) BMDM. Thus cathepsin G activity may impair efferocytosis, which could lead to an accumulation of lesion-associated apoptotic cells and the accelerated progression of early atherosclerotic lesions to more complex lesions in Apoe(-/-) mice.
Hypertension Unit, University of Ottawa Heart Institute, Ottawa, Ontario, Canada;
Naimeh
N
Rafatian
Denuja
D
Karunakaran
Katey J
KJ
Rayner
Frans H H
FH
Leenen
Ross W
RW
Milne
Stewart C
SC
Whitman
D000804:Angiotensin II / Q000096:biosynthesis; D000818:Animals; D001011:Aorta / Q000473:pathology*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics*; D017209:Apoptosis / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics* / Q000473:pathology; D056649:Cathepsin G / Q000235:genetics*; D059305:Diet, High-Fat; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010587:Phagocytosis / Q000235:genetics*; D058226:Plaque, Atherosclerotic / Q000235:genetics* / Q000473:pathology
D001057:Apolipoproteins E; D000804:Angiotensin II; D056649:Cathepsin G; C534096:Ctsg protein, mouse
Apo E; atherosclerosis; cathepsin G; lesion progression