title: CCR2 mediates the uptake of bone marrow-derived fibroblast precursors in angiotensin II-induced cardiac fibrosis.
abstract: Angiotensin II plays an important role in the development of cardiac hypertrophy and fibrosis, but the underlying cellular and molecular mechanisms are not completely understood. Recent studies have shown that bone marrow-derived fibroblast precursors are involved in the pathogenesis of cardiac fibrosis. Since bone marrow-derived fibroblast precursors express chemokine receptor, CCR2, we tested the hypothesis that CCR2 mediates the recruitment of fibroblast precursors into the heart, causing angiotensin II-induced cardiac fibrosis. Wild-type and CCR2 knockout mice were infused with angiotensin II at 1,500 ng·kg(-1)·min(-1). Angiotensin II treatment resulted in elevated blood pressure and cardiac hypertrophy that were not significantly different between wild-type and CCR2 knockout mice. Angiotensin II treatment of wild-type mice caused prominent cardiac fibrosis and accumulation of bone marrow-derived fibroblast precursors expressing the hematopoietic markers, CD34 and CD45, and the mesenchymal marker, collagen I. However, angiotensin II-induced cardiac fibrosis and accumulation of bone marrow-derived fibroblast precursors in the heart were abrogated in CCR2 knockout mice. Furthermore, angiotensin II treatment of wild-type mice increased the levels of collagen I, fibronectin, and α-smooth muscle actin in the heart, whereas these changes were not observed in the heart of angiotensin II-treated CCR2 knockout mice. Functional studies revealed that the reduction of cardiac fibrosis led to an impairment of cardiac systolic function and left ventricular dilatation in angiotensin II-treated CCR2 knockout mice. Our data demonstrate that CCR2 plays a pivotal role in the pathogenesis of angiotensin II-induced cardiac fibrosis through regulation of bone marrow-derived fibroblast precursors.
authors.affiliation: Division of Nephrology, Department of Medicine, Changhai Hospital, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.forename: Song-Chang
authors.initials: SC
authors.lastname: Lin
authors.forename: Jiyuan
authors.initials: J
authors.lastname: Chen
authors.forename: Yuanxin
authors.initials: Y
authors.lastname: Miao
authors.forename: George E
authors.initials: GE
authors.lastname: Taffet
authors.forename: Mark L
authors.initials: ML
authors.lastname: Entman
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000704:Analysis of Variance; D000804:Angiotensin II; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001794:Blood Pressure; D001854:Bone Marrow Cells / Q000378:metabolism*; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism; D002465:Cell Movement; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism*; D005355:Fibrosis; D006331:Heart Diseases / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D006339:Heart Rate; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D054390:Receptors, CCR2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism*; D013318:Stroke Volume; D013997:Time Factors; D014463:Ultrasonography; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000378:metabolism; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: D015415:Biomarkers; C515335:Ccr2 protein, mouse; D054390:Receptors, CCR2; D000804:Angiotensin II