title: Cardiac transgenic matrix metalloproteinase-2 expression directly induces impaired contractility.
abstract: 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 microm 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 approximately 50% of WT, suggesting a myofilament contraction defect.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Radiology, University of California, San Francisco, USA
authors.forename: Guan-Ying
authors.initials: GY
authors.lastname: Wang
authors.forename: Marina R
authors.initials: MR
authors.lastname: Bergman
authors.forename: Anita P
authors.initials: AP
authors.lastname: Nguyen
authors.forename: Sally
authors.initials: S
authors.lastname: Turcato
authors.forename: Philip M
authors.initials: PM
authors.lastname: Swigart
authors.forename: Manoj C
authors.initials: MC
authors.lastname: Rodrigo
authors.forename: Paul C
authors.initials: PC
authors.lastname: Simpson
authors.forename: Joel S
authors.initials: JS
authors.lastname: Karliner
authors.forename: David H
authors.initials: DH
authors.lastname: Lovett
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Baker
mesh_terms: D008841:Actin Cytoskeleton / Q000648:ultrastructure; D000262:Adenylyl Cyclases / Q000378:metabolism; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D004558:Electric Stimulation; D004721:Endoplasmic Reticulum / Q000648:ultrastructure; D005347:Fibroblasts / Q000648:ultrastructure; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D009200:Myocardial Contraction; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism / Q000648:ultrastructure*; D012518:Sarcomeres / Q000648:ultrastructure; D013268:Stimulation, Chemical; D018487:Ventricular Dysfunction, Left / Q000201:enzymology / Q000503:physiopathology; D020257:Ventricular Remodeling
chemical_list: D000319:Adrenergic beta-Antagonists; D005576:Colforsin; D020778:Matrix Metalloproteinase 2; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D002118:Calcium