Copyright © 2005, European Society of Cardiology
Cardiac transgenic matrix metalloproteinase-2 expression directly induces impaired contractility
aDepartment of Radiology, University of California, San Francisco, United States
bDepartment of Medicine, University of California, San Francisco, United States
cCardiovascular Research Institute, University of California, San Francisco, United States
dVeterans Affairs Medical Center, San Francisco, United States
* Corresponding author. University of California, San Francisco, VA Medical Center, Cardiology Division (111C), 4150 Clement St, San Francisco, CA 94121, United States. Tel.: +1 415 221 4810x4790; fax: +1 415 750 6950. Email address: ajbaker{at}itsa.ucsf.edu
Objective: Matrix metalloproteinase-2 (MMP-2) plays a major role in dysfunctional ventricular remodeling following myocardial injury induced by ischemia/reperfusion and heart failure. To directly assess the role of MMP-2 in the absence of superimposed injury, we generated cardiac-specific, constitutively active MMP-2 transgenic mice.
Methods: Morphologic and functional studies were carried out using both intact and demembranated (skinned) right ventricular trabeculae dissected from hearts of 8-month-old MMP-2 transgenic mice and wild-type controls (WT).
Results: Electron micrographs showed that compared to WT, MMP-2 myocardium had no gross, ultrastructural changes (no myocyte dropout or gross fibrosis). However, MMP-2 myocardium contained fibroblasts with abundant rough endoplasmic reticulum, consistent with an activated synthetic phenotype, suggesting extracellular matrix remodeling in MMP-2 trabeculae. Consistent with remodeling, mechanical studies found increased stiffness of intact unstimulated trabeculae (increasing sarcomere lengths from 2 to 2.3 µm caused a greater rise of passive muscle force for MMP-2 trabeculae versus WT). With electrical stimulation, MMP-2 trabeculae generated substantially less active force at all sarcomere lengths. Moreover, inotropic responses to increases of bath [Ca2+], pacing frequency, and isoproterenol were all significantly reduced versus WT trabeculae. Skinned fiber assessment of myofilament function revealed that maximum Ca2+-activated force of skinned MMP-2 trabeculae was reduced to 
50% of WT, suggesting a myofilament contraction defect.
Conclusion: Cardiac-specific, constitutively active MMP-2 expression leads to impaired contraction and diminished responses to inotropic stimulation. These findings indicate that MMP-2 can directly impair ventricular function in the absence of superimposed injury.
KEYWORDS Extracellular matrix; Transgenic mouse; Remodeling; Contractile function; Trabeculae