Differential role of TIMP2 and TIMP3 in cardiac hypertrophy, fibrosis, and diastolic dysfunction

Cardiovasc Res. 2014 Jul 15;103(2):268-80. doi: 10.1093/cvr/cvu072. Epub 2014 Apr 1.

Abstract

Aims: Tissue inhibitor of metalloproteinases (TIMPs) can mediate myocardial remodelling, hypertrophy, and fibrosis in heart disease. We investigated the impact of TIMP2 vs. TIMP3 deficiency in angiotensin II (Ang II)-induced myocardial remodelling and cardiac dysfunction.

Methods and results: TIMP2(-/-), TIMP3(-/-), and wild-type (WT) mice received Ang II/saline (Alzet pump) for 2 weeks. Ang II infusion resulted in enhanced myocardial hypertrophy and lack of fibrosis in TIMP2(-/-), and conversely, excess fibrosis without hypertrophy in TIMP3(-/-) mice. Echocardiographic imaging revealed preserved ejection fraction in all groups; however, exacerbated left ventricular (LV) diastolic dysfunction was detected in Ang II-infused TIMP2(-/-) and TIMP3(-/-) mice, despite the suppressed Ang II-induced hypertension in TIMP3(-/-) mice. Enhanced hypertrophy in TIMP2(-/-) mice impaired active relaxation, while excess fibrosis in TIMP3(-/-) mice increased LV passive stiffness. Adult WT cardiomyocytes, only when co-cultured with cardiac fibroblasts, exhibited Ang II-induced hypertrophy which was suppressed in TIMP3(-/-) cardiomyocytes. In vitro studies on adult cardiofibroblasts (quiescent and cyclically stretched), and in vivo analyses, revealed that the increased fibrosis in TIMP3(-/-)-Ang II hearts is due to post-translational stabilization and deposition of collagen by matricellular proteins [osteopontin and Secreted Protein Acidic and Rich in Cysteine (SPARC)], which correlated with increased inflammation, rather than increased de novo synthesis. Reduced cross-linking enzymes, LOX and PLOD1, could underlie suppressed collagen deposition in TIMP2(-/-)-Ang II hearts.

Conclusion: TIMP2 and TIMP3 play fundamental and differential roles in mediating pathological remodelling, independent from their MMP-inhibitory function. TIMP2(-/-) and TIMP3(-/-) mice provide a unique opportunity to study myocardial hypertrophy and fibrosis independently, and their impact on cardiac dysfunction.

Keywords: Cardiac fibroblast; Diastolic dysfunction; Extracellular matrix; Fibrosis; Hypertrophy; Matricellular proteins; Tissue inhibitor of metalloproteinase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / metabolism*
  • Animals
  • Cardiomegaly / enzymology*
  • Cardiomegaly / genetics
  • Cardiomegaly / physiopathology
  • Cardiomyopathies / genetics
  • Fibrosis / genetics
  • Heart Failure, Diastolic / enzymology*
  • Heart Failure, Diastolic / genetics
  • Heart Failure, Diastolic / physiopathology
  • Hypertrophy, Left Ventricular / genetics*
  • Hypertrophy, Left Ventricular / physiopathology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardium / metabolism
  • Tissue Inhibitor of Metalloproteinase-2 / genetics*
  • Tissue Inhibitor of Metalloproteinase-3 / genetics*
  • Ventricular Remodeling / genetics

Substances

  • Tissue Inhibitor of Metalloproteinase-3
  • Angiotensin II
  • Tissue Inhibitor of Metalloproteinase-2