Reduced MMP-2 activity contributes to cardiac fibrosis in experimental diabetic cardiomyopathy

Basic Res Cardiol. 2008 Jul;103(4):319-27. doi: 10.1007/s00395-008-0715-2. Epub 2008 Mar 17.


Objective: To evaluate the regulation of matrix metalloproteinase (MMP)-2 in diabetic cardiomyopathy.

Methods: Left ventricle (LV) function was determined by a micro-tip catheter in streptozotocin (STZ)-induced diabetic rats, 2 or 6 weeks (w) after STZ-application. LV total collagen, collagen type I and III content were immunohistologically analyzed and quantified by digital image analysis. LV collagen type I, III and MMP-2 mRNA expression was quantified by real-time RT-PCR. LV pro- and active MMP-2 levels were analyzed by zymography; Smad 7, membrane type (MT)1-MMP and tissue inhibitor metalloproteinase (TIMP)-2 protein levels by Western Blot.

Results: STZ-induced diabetes was associated with a time-dependent impairment of LV diastolic and systolic function. This was paralleled by a time-dependent increase in LV total collagen content, despite reduced LV collagen type I and III mRNA levels, indicating a role of post-transcriptional/post-translational changes of extracellular matrix regulation. Six weeks (w) after STZ-injection, MMP-2 mRNA expression and pro-MMP-2 levels were 2.7-fold (P < 0.005) and 1.3-fold (P < 0.05) reduced versus controls, respectively, whereas active MMP-2 was decreased to undetectable levels 6 w post-STZ. Concomitantly, Smad 7 and TIMP-2 protein levels were 1.3-fold (P < 0.05) and 10-fold (P < 0.005) increased in diabetics versus controls, respectively, whereas the 45 kDa form of MT1-MMP was undetectable in diabetics.

Conclusion: Under STZ-diabetic conditions, cardiac fibrosis is associated with a dysregulation in extracellular matrix degradation. This condition is featured by reduced MMP-2 activity, concomitant with increased Smad 7 and TIMP-2 and decreased MT1-MMP protein expression, which differs from mechanisms involved in dilated and ischemic heart disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiomyopathies / enzymology
  • Cardiomyopathies / pathology*
  • Collagen / metabolism
  • Diabetes Complications / enzymology
  • Diabetes Complications / pathology*
  • Diabetes Mellitus, Experimental / complications*
  • Diabetes Mellitus, Experimental / enzymology
  • Diabetes Mellitus, Experimental / pathology
  • Fibrosis
  • Male
  • Matrix Metalloproteinase 14 / analysis
  • Matrix Metalloproteinase 2 / analysis
  • Matrix Metalloproteinase 2 / genetics
  • Matrix Metalloproteinase 2 / physiology*
  • Matrix Metalloproteinase 9 / genetics
  • Myocardium / pathology*
  • RNA, Messenger / analysis
  • Rats
  • Rats, Sprague-Dawley
  • Smad7 Protein / analysis
  • Streptozocin
  • Tissue Inhibitor of Metalloproteinase-2 / analysis
  • Transforming Growth Factor beta / analysis


  • RNA, Messenger
  • Smad7 Protein
  • Smad7 protein, rat
  • Transforming Growth Factor beta
  • Tissue Inhibitor of Metalloproteinase-2
  • Streptozocin
  • Collagen
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9
  • Matrix Metalloproteinase 14