title: Inhibiting matrix metalloproteinase by cell-based timp-3 gene transfer effectively treats acute and chronic ischemic cardiomyopathy.
abstract: After a myocardial infarction (MI), an increase in the cardiac ratio of matrix metalloproteinases (MMPs) relative to their inhibitors (TIMPs) causes extracellular matrix modulation that leads to ventricular dilatation and congestive heart failure. Cell therapy can mitigate these effects.  In this study, we tested whether increasing MMP inhibition via cell-based gene transfer of Timp-3 further preserved ventricular morphometry and cardiac function in a rat model of MI. We also measured the effect of treatment timing. We generated MI (coronary artery ligation) in adult  rats. Three or 14 days later, we implanted medium (control) or vascular smooth muscle cells transfected with empty vector (VSMCs) or Timp-3 (C-TIMP-3) into the peri-infarct region (n = 15-24/group). We assessed MMP-2 and -9 expression and activity, TIMP-3, and TNF-α  expression, cell apoptosis, infarct size and thickness, ventricular morphometry, and cardiac function (by echocardiography). Relative to medium, VSMCs delivered at either time point significantly reduced cardiac expression and activity of MMP-2 and -9, reduced expression of TNF-α, and  increased expression of TIMP-3. Cell therapy also reduced apoptosis and scar area, increased infarct thickness, preserved ventricular structure, and reduced functional loss. All these effects were augmented by C-TIMP-3 treatment. Survival and cardiac function were significantly greater when  VSMCs or C-TIMP-3 were delivered at 3 (vs. 14) days after MI. Upregulating post-MI cardiac TIMP-3 expression via cell-based gene therapy contributed additional regulation of MMP, TIMP, and TNF-α levels, thereby boosting the structural and functional effects of VSMCs transplanted at 3  or 14 days after an MI in rats. Early treatment may be superior to late, though both are effective.
authors.affiliation: Department of Cardiovascular Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China. hai_tianhai@yahoo.com
authors.forename: Hai
authors.initials: H
authors.lastname: Tian
authors.forename: Ming-Li
authors.initials: ML
authors.lastname: Huang
authors.forename: Kai-Yu
authors.initials: KY
authors.lastname: Liu
authors.forename: Zhi-Bo
authors.initials: ZB
authors.lastname: Jia
authors.forename: Lu
authors.initials: L
authors.lastname: Sun
authors.forename: Shu-Lin
authors.initials: SL
authors.lastname: Jiang
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Heather Y
authors.initials: HY
authors.lastname: McDonald Kinkaid
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.forename: Ren-Ke
authors.initials: RK
authors.lastname: Li
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D064987:Cell- and Tissue-Based Therapy; D002478:Cells, Cultured; D002908:Chronic Disease; D004195:Disease Models, Animal; D004452:Echocardiography; D005260:Female; D006352:Heart Ventricles / Q000503:physiopathology / Q000648:ultrastructure; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D009203:Myocardial Infarction / Q000401:mortality / Q000503:physiopathology / Q000628:therapy*; D051381:Rats; D017208:Rats, Wistar; D015996:Survival Rate; D013997:Time Factors; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D019717:Tissue Inhibitor of Metalloproteinase-3; D014409:Tumor Necrosis Factor-alpha; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9