title: Matrix metalloproteinase-2 mediates a mechanism of metabolic cardioprotection consisting of negative regulation of the sterol regulatory element-binding protein-2/3-hydroxy-3-methylglutaryl-CoA reductase pathway in the heart.
abstract: Previously, we reported that cardiac matrix metalloproteinase (MMP)-2 is upregulated in hypertensive mice. How MMP-2 affects the development of cardiac disease is unclear. Here, we report that MMP-2 protects from hypertensive cardiac disease. In mice infused with angiotensin II, the lack of MMP-2 (Mmp2(-/-)) did not affect the severity of the hypertension but caused cardiac hypertrophy to develop earlier and to a greater extent versus wild-type (Mmp2(+/+)) mice, as measured by heart weight:body weight ratio and upregulation of hypertrophy and fibrosis markers. We further found numerous metabolic and inflammatory gene expression abnormalities in the left ventricle of Mmp2(-/-) mice. Interestingly, Mmp2(-/-) mice expressed greater amounts of sterol regulatory element-binding protein-2 and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (a target of sterol regulatory element-binding protein-2-mediated transcription and rate limiting enzyme in cholesterol and isoprenoids biosynthesis) in addition to markers of inflammation including chemokines of the C-C motif ligand family. We focused on the functionally related genes for sterol regulatory binding protein-2 and 3-hydroxy-3-methylglutaryl-coenzyme A reductase. The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, lovastatin, attenuated angiotensin II-induced cardiac hypertrophy and fibrosis in Mmp2(-/-) and wild-type (Mmp2(+/+)) mice, with Mmp2(-/-) mice showing resistance to cardioprotection by lovastatin. MMP-2 deficiency predisposes to cardiac dysfunction as well as metabolic and inflammatory gene expression dysregulation. This complex phenotype is, at least in part, because of the cardiac sterol regulatory element-binding protein-2/3-hydroxy-3-methylglutaryl-coenzyme A reductase pathway being upregulated in MMP-2 deficiency.
authors: From the Departments of Biochemistry (X.W., E.B., S.H.-A., C.F.-P.) and Physiology (A.T., Z.K.), Mazankowski Alberta Heart Institute (Z.K., C.F.-P.), Cardiovascular Research Group (Z.K., C.F.-P.), and Faculty of Medicine and Dentistry (X.W., E.B., S.H.-A., C.F.-P.), University of Alberta, Edmonton, Alberta, Canada.
authors: Xiang
authors: X
authors: Wang
authors: From the Departments of Biochemistry (X.W., E.B., S.H.-A., C.F.-P.) and Physiology (A.T., Z.K.), Mazankowski Alberta Heart Institute (Z.K., C.F.-P.), Cardiovascular Research Group (Z.K., C.F.-P.), and Faculty of Medicine and Dentistry (X.W., E.B., S.H.-A., C.F.-P.), University of Alberta, Edmonton, Alberta, Canada.
authors: Evan
authors: E
authors: Berry
authors: From the Departments of Biochemistry (X.W., E.B., S.H.-A., C.F.-P.) and Physiology (A.T., Z.K.), Mazankowski Alberta Heart Institute (Z.K., C.F.-P.), Cardiovascular Research Group (Z.K., C.F.-P.), and Faculty of Medicine and Dentistry (X.W., E.B., S.H.-A., C.F.-P.), University of Alberta, Edmonton, Alberta, Canada.
authors: Samuel
authors: S
authors: Hernandez-Anzaldo
authors: From the Departments of Biochemistry (X.W., E.B., S.H.-A., C.F.-P.) and Physiology (A.T., Z.K.), Mazankowski Alberta Heart Institute (Z.K., C.F.-P.), Cardiovascular Research Group (Z.K., C.F.-P.), and Faculty of Medicine and Dentistry (X.W., E.B., S.H.-A., C.F.-P.), University of Alberta, Edmonton, Alberta, Canada.
authors: Abhijit
authors: A
authors: Takawale
authors: From the Departments of Biochemistry (X.W., E.B., S.H.-A., C.F.-P.) and Physiology (A.T., Z.K.), Mazankowski Alberta Heart Institute (Z.K., C.F.-P.), Cardiovascular Research Group (Z.K., C.F.-P.), and Faculty of Medicine and Dentistry (X.W., E.B., S.H.-A., C.F.-P.), University of Alberta, Edmonton, Alberta, Canada.
authors: Zamaneh
authors: Z
authors: Kassiri
authors: From the Departments of Biochemistry (X.W., E.B., S.H.-A., C.F.-P.) and Physiology (A.T., Z.K.), Mazankowski Alberta Heart Institute (Z.K., C.F.-P.), Cardiovascular Research Group (Z.K., C.F.-P.), and Faculty of Medicine and Dentistry (X.W., E.B., S.H.-A., C.F.-P.), University of Alberta, Edmonton, Alberta, Canada. cf2@ualberta.ca.
authors: Carlos
authors: C
authors: Fernandez-Patron
mesh_terms: D000214:Acyl Coenzyme A / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D001794:Blood Pressure; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D015151:Immunoblotting; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D012313:RNA / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D051782:Sterol Regulatory Element Binding Protein 2 / Q000096:biosynthesis / Q000235:genetics*; D014157:Transcription Factors
chemical_list: D000214:Acyl Coenzyme A; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors; C008047:3-hydroxy-3-methylglutaryl-coenzyme A; D012313:RNA; D020778:Matrix Metalloproteinase 2
keywords: cardiomegaly; hydroxymethylglutaryl-CoA reductase inhibitors; matrix metalloproteinase 2; sterol regulatory element binding proteins