title: Targeted deletion of matrix metalloproteinase 2 ameliorates myocardial remodeling in mice with chronic pressure overload.
abstract: Matrix metalloproteinases (MMPs) play an important role in the extracellular matrix remodeling. Experimental and clinical studies have demonstrated that MMP 2 and 9 are upregulated in the dilated failing hearts and involved in the development and progression of myocardial remodeling. However, little is known about the role of MMPs in mediating adverse myocardial remodeling in response to chronic pressure overload (PO). We, thus, hypothesized that selective disruption of the MMP 2 gene could ameliorate PO-induced cardiac hypertrophy and dysfunction in mice. PO hypertrophy was induced by transverse aortic constriction (TAC) in male MMP 2 knockout (KO) mice (n=10) and sibling wild-type (WT) mice (n=9). At 6 weeks, myocardial MMP 2 zymographic activity was 2.4-fold increased in WT+TAC, and this increase was not observed in KO+TAC, with no significant alterations in other MMPs (MMP 1, 3, 8, and 9) or tissue inhibitors of MMPs (1, 2, 3, and 4). TAC resulted in a significant increase in left ventricular (LV) weight and LV end-diastolic pressure (EDP) with preserved systolic function. KO+TAC mice exerted significantly lower LV weight/body weight (4.2+/-0.2 versus 5.0+/-0.2 mg/g; P<0.01), lung weight/body weight (4.9+/-0.2 versus 6.2+/-0.4 mg/g; P<0.01), and LV end-diastolic pressure (4+/-1 versus 10+/-2 mm Hg; P<0.05) than WT+TAC mice despite comparable aortic pressure. KO+TAC mice had less myocyte hypertrophy (cross-sectional area; 322+/-14 versus 392+/-14 microm2; P<0.01) and interstitial fibrosis (collagen volume fraction; 3.3+/-0.5 versus 8.2+/-1.0%; P<0.01) than WT+TAC mice. MMP 2 plays an important role in PO-induced LV hypertrophy and dysfunction. The inhibition of MMP 2 activation may, therefore, be a useful therapeutic strategy to manage hypertensive heart disease.
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. htsutsui@med.hokudai.ac.jp
authors.forename: Hidenori
authors.initials: H
authors.lastname: Matsusaka
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ide
authors.forename: Shouji
authors.initials: S
authors.lastname: Matsushima
authors.forename: Masaki
authors.initials: M
authors.lastname: Ikeuchi
authors.forename: Toru
authors.initials: T
authors.lastname: Kubota
authors.forename: Kenji
authors.initials: K
authors.lastname: Sunagawa
authors.forename: Shintaro
authors.initials: S
authors.lastname: Kinugawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsutsui
mesh_terms: D000818:Animals; D001011:Aorta; D006332:Cardiomegaly / Q000000981:diagnostic imaging* / Q000209:etiology / Q000473:pathology; D002908:Chronic Disease; D003094:Collagen / Q000378:metabolism; D003251:Constriction, Pathologic; D004452:Echocardiography; D005355:Fibrosis; D017353:Gene Deletion; D006439:Hemodynamics; D006973:Hypertension / Q000150:complications / Q000235:genetics / Q000503:physiopathology*; D008168:Lung / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D020257:Ventricular Remodeling
chemical_list: D012333:RNA, Messenger; D003094:Collagen; D020778:Matrix Metalloproteinase 2