title: Transgenic MMP-2 expression induces latent cardiac mitochondrial dysfunction.
abstract: Matrix metalloproteinases (MMPs) are central to the development and progression of dysfunctional ventricular remodeling after tissue injury. We studied 6 month old heterozygous mice with cardiac-specific transgenic expression of active MMP-2 (MMP-2 Tg). MMP-2 Tg hearts showed no substantial gross alteration of cardiac phenotype compared to age-matched wild-type littermates. However, buffer perfused MMP-2 Tg hearts subjected to 30 min of global ischemia followed by 30 min of reperfusion had a larger infarct size and greater depression in contractile performance compared to wild-type hearts. Importantly, cardioprotection mediated by ischemic preconditioning (IPC) was completely abolished in MMP-2 Tg hearts, as shown by abnormalities in mitochondrial ultrastructure and impaired respiration, increased lipid peroxidation, cell necrosis and persistently reduced recovery of contractile performance during post-ischemic reperfusion. We conclude that MMP-2 functions not only as a proteolytic enzyme but also as a previously unrecognized active negative regulator of mitochondrial function during superimposed oxidative stress.
authors.affiliation: Cardiology Section, Department of Medicine, UCSF, VA Medical Center, 4150 Clement Street, 111C-5, San Francisco, CA 94121, USA.
authors.forename: Hui-Zhong
authors.initials: HZ
authors.lastname: Zhou
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Ma
authors.forename: Mary O
authors.initials: MO
authors.lastname: Gray
authors.forename: Bo-qing
authors.initials: BQ
authors.lastname: Zhu
authors.forename: Anita P
authors.initials: AP
authors.lastname: Nguyen
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Baker
authors.forename: Ursula
authors.initials: U
authors.lastname: Simonis
authors.forename: Gary
authors.initials: G
authors.lastname: Cecchini
authors.forename: David H
authors.initials: DH
authors.lastname: Lovett
authors.forename: Joel S
authors.initials: JS
authors.lastname: Karliner
mesh_terms: D000818:Animals; D003402:Creatine Kinase / Q000378:metabolism; D006579:Heterozygote; D019157:Ischemic Preconditioning, Myocardial; D015227:Lipid Peroxidation; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000201:enzymology / Q000502:physiology*; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology / Q000648:ultrastructure; D009336:Necrosis
chemical_list: D003402:Creatine Kinase; D020778:Matrix Metalloproteinase 2