Tissue Inhibitor of Metalloproteinase‐2 Gene Delivery Ameliorates Postinfarction Cardiac Remodeling

Abstract

HYPOTHESIS: Adenoviral-mediated (AdV-T2) overexpression of TIMP-2 would blunt ventricular remodeling and improve survival in a murine model of chronic ischemic injury. METHODS: Male mice (n = 124) aged 10-14 weeks underwent either (1) left coronary artery ligation to induce myocardial infarction (MI group, n = 36), (2) myocardial injection of 6 × 10¹⁰ viral particles of AdV-T2 immediately post-MI (MI + T2 group, n = 30), (3) myocardial injection of 6 × 10¹⁰ viral particles of a control adenovirus (MI + Ct, n = 38), or 4) received no intervention (controls, n = 20). On post-MI day 7, surviving mice (n = 79) underwent echocardiographic, immunohistochemical, and biochemical analysis. RESULTS: In infarcted animals, the MI + T2 group demonstrated improved survival (p < 0.02), better preservation of developed pressure and ventricular diameter (p < 0.04), and the lowest expression and activity of MMP-2 and MMP-9 (p < 0.04) compared with MI and MI + Ct groups. All infarcted hearts displayed significantly increased inflammatory cell infiltration (p < 0.04 vs. control, MI, or MI + T2), with infiltration highest in the MI + Ct group and lowest in the MI + T2 group (p < 0.04). CONCLUSIONS: Adenoviral mediated myocardial delivery of the TIMP-2 gene improves post-MI survival and limits adverse remodeling in a murine model of MI.