O46	Peri-infarct gene transfer of human tissue kallikrein gene prevents left ventricle dysfunction by stimulating angiogenesis/arteriogenesis and cardiac stem cell activation and by inhibiting cardiomyocyte apoptosis.
1F.Spillmann, 3G.Graiani, 1S.Van Linthout, 1M.Meloni, 2D.Westermann, 1I.Campesi, 3C.Lagrasta, 2C.Tschope, 4C.Emanueli, 4P.Madeddu
1Experimental Medicine and Gene Therapy Section, INBB, Sassari, IT; 23Department of Cardiology and Pneumonology, Charité-University Medicine of Berlin, Berlin, DE; 3Department of Pathology, University of Parma, Parma, IT; 4University of Bristol, Bristol, GB.

Gene deletion/insertion studies support a role for the kallikrein-kinin system in the control of myocardial vascularization and function. We hypothesized that human tissue kallikrein (hTK) gene transfer could foster myocardial neovascularization and cardiomyocyte survival/regeneration, thus preventing post-infarct left ventricle (LV) dysfunction. An adenoviral vector carrying hTK cDNA (Ad.hTK, 10<7> p.f.u./10 µl) or harbouring no transgene (Ad.Null) or saline (NaCl) was injected into the area at risk at the occasion of operative occlusion of left coronary artery. Survival rate was similar among groups. Transduction of heterologous protein was limited to the peri-infarct zone. At 5 weeks post-myocardial infarction (MI), indexes of systolic and diastolic function were improved in Ad.hTK compared with Ad.Null or NaCl group (P<0.05 for both comparisons). Morphometric/histologic analysis indicates that hTK stimulates capillary and arteriole growth in the area at risk and protects the heart from post-MI hypertrophic remodelling (P<0.05 vs. Ad.Null or NaCl group). In addition, hTK benefits the survival of peri-infarct cardiomyocytes and confers them with greater resistance to apoptosis triggered by ex vivo Angiotensin II challenge (P<0.05 vs. Ad.Null or NaCl). A higher abundance of c-kit-positive, CD45-/CD68-negative cells was detected in the area at risk of hTK-injected hearts (P<0.01 vs. Ad.Null). Expressional studies indicate activation of pro-angiogenic, prosurvival Akt-eNOS-Bcl2 pathway and inhibition of pro-apoptotic caspase 3 pathway in hTK-transduced hearts. Thus, peri-infarct gene transfer of hTK gene prevents LV dysfunction by stimulating angiogenesis/arteriogenesis and cardiomyocyte survival/regeneration. These results support efficacy of early biological revascularization of the ischemic heart for prevention of post-MI cardiac dysfunction.

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