Transgenic MMP-2 expression induces latent cardiac mitochondrial dysfunction.
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.
Zhou
Hui-Zhong
HZ
Cardiology Section, Department of Medicine, UCSF, VA Medical Center, 4150 Clement Street, 111C-5, San Francisco, CA 94121, USA.
Ma
Xiaokui
X
Gray
Mary O
MO
Zhu
Bo-qing
BQ
Nguyen
Anita P
AP
Baker
Anthony J
AJ
Simonis
Ursula
U
Cecchini
Gary
G
Lovett
David H
DH
Karliner
Joel S
JS
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
D003402:Creatine Kinase; D020778:Matrix Metalloproteinase 2