title: Cardiac function is not significantly diminished in hearts isolated from young caveolin-1 knockout mice.
abstract: Matrix metalloproteinases (MMPs) are known to degrade components of the extracellular matrix. More recently, in myocardial oxidative stress injury including ischemia-reperfusion, MMP-2 is activated and degrades troponin I and α-actinin. MMP activity is regulated at several levels. We recently showed that MMP-2 is localized in the caveolae of cardiomyocytes and is negatively regulated by caveolin-1 (Cav-1). The caveolin scaffolding domain of Cav-1 inhibits MMP-2 proteolytic activity in vitro, and Cav-1(-/-) mouse hearts have increased MMP-2 activity compared with controls. Whether this increase in MMP-2 activity translates to impaired cardiac function is unknown. Hearts isolated from Cav-1(-/-) mice and their wild-type controls were perfused as isolated working hearts and physiologically challenged with increasing increments of left atrial preload (7-22.5 mmHg). The hearts were then pharmacologically challenged with increasing concentrations of isoproterenol (0.1-100 nM). Functionally, the Cav-1(-/-) hearts were similar to the controls in heart rate, peak systolic pressure, developed pressure, and rate pressure product. At higher preload pressures, the Cav-1(-/-) hearts outperformed the control hearts. Coronary flow was significantly higher in Cav-1(-/-) hearts under all conditions. The highest concentration of isoproternol increased the heart rate of Cav-1(-/-) hearts more than in controls. Western blot analysis revealed no significant changes in troponin I or α-actinin between Cav-1(-/-) hearts and their controls. There was a significant loss of MMP-2 from both knockout and control hearts during the perfusion. In summary, despite the loss of Cav-1, Cav-1(-/-) hearts show similar or better cardiac function compared with wild-type hearts following physiological challenge or β-adrenergic stimulation in vitro, and this appears unrelated to changes in MMP-2.
authors.affiliation: Department of Pediatrics, Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Ava K
authors.initials: AK
authors.lastname: Chow
authors.forename: Edwin E
authors.initials: EE
authors.lastname: Daniel
authors.forename: Richard
authors.initials: R
authors.lastname: Schulz
mesh_terms: D000185:Actinin / Q000378:metabolism; D000818:Animals; D002302:Cardiac Output / Q000187:drug effects / Q000502:physiology*; D002316:Cardiotonic Agents / Q000494:pharmacology; D051242:Caveolin 1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009206:Myocardium / Q000378:metabolism; D019210:Troponin I / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; D051242:Caveolin 1; D019210:Troponin I; D000185:Actinin; D020778:Matrix Metalloproteinase 2; D007545:Isoproterenol