title: Activation of MMP8 and MMP13 by angiotensin II correlates to severe intra-plaque hemorrhages and collagen breakdown in atherosclerotic lesions with a vulnerable phenotype.
abstract: Angiotensin II (ATII)-mediated hypertension increases the risk for acute coronary events, which may be caused by augmented collagen degradation. Interstitial fibers of collagen type I in the plaque can be degraded by MMP8 and MMP13 specifically. Indeed high MMP8 levels have been correlated with ruptured plaques in patients. To study the contribution of ATII in plaque rupture, we evaluated its effect on MMP8 and MMP13 activity on the vulnerable lesions using an extravascular device that induces regions of pro-atherogenic shear stress in the carotid arteries of ApoE KO mice. This triggers the growth of lesions with a "vulnerable" macrophage-rich phenotype (referred to as upstream lesions) and lesions with a "stable" fibrotic phenotype (referred to as downstream lesions). ATII administration increased mean blood pressure, and increased the incidence of intra-plaque hemorrhages (IPH) from 30% to 73% of the animals in the upstream segments. The area of IPH was also increased by 5-fold. No IPHs were observed in the downstream lesions of the control group or the ATII group. In addition, ATII treatment doubled the size of upstream and downstream lesions. Upstream lesions in the ATII group were decreased in collagen content by 3-fold, contained 2-fold higher MMP8 and MMP13 levels, with a 2- and 3-fold increase in collagen type I degradation by MMP8 and MMP13 respectively compared to the upstream lesions in the control group. Gene expression analysis showed general increase in procollagens and TIMPs expression in response to ATII. However, ATII also decreased procollagen 5alpha3 expression in downstream lesions and decreased TIMP4 expression in upstream lesions. These data show that ATII promotes a "stable" fibrotic phenotype by inducing severe intra-plaque hemorrhages, characterized by increased degradation of interstitial collagen I via an MMP-mediated (MMP8 and MMP13) mechanism.
authors.affiliation: Department of Cardiology, Thoraxcenter, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Caroline
authors.initials: C
authors.lastname: Cheng
authors.forename: Dennie
authors.initials: D
authors.lastname: Tempel
authors.forename: Rien
authors.initials: R
authors.lastname: van Haperen
authors.forename: Luc
authors.initials: L
authors.lastname: van Damme
authors.forename: Meryem
authors.initials: M
authors.lastname: Algür
authors.forename: Rob
authors.initials: R
authors.lastname: Krams
authors.forename: Rini
authors.initials: R
authors.lastname: de Crom
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001794:Blood Pressure; D002340:Carotid Artery Diseases / Q000150:complications / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D017536:Carotid Artery, Common / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005355:Fibrosis; D020869:Gene Expression Profiling; D006470:Hemorrhage / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D015918:Infusion Pumps, Implantable; D055104:Infusions, Subcutaneous; D008264:Macrophages / Q000201:enzymology / Q000473:pathology; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism*; D020784:Matrix Metalloproteinase 8 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011347:Procollagen / Q000235:genetics / Q000378:metabolism*; D012720:Severity of Illness Index; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D024042:Collagen Type I; D011347:Procollagen; D019714:Tissue Inhibitor of Metalloproteinases; D000804:Angiotensin II; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse; D020784:Matrix Metalloproteinase 8