Abstract 1588: Midkine Gene Transfer Ameliorates Ischemic Cardiomyopathy through Enhancements of Neovascularization via Akt/PI3 Kinase and ERK Pathways and Anti-Apoptosis by Regulating Bcl-2 and Bax
Midkine (MK) is a heparin-binding growth factor involved in diverse biological phenomena, e.g. neural survival, carcinogenesis and tissue repair. We have demonstrated recently that MK ameliorates acute myocardial injury by ischemia/reperfusion through prevention of apoptotic reactions. Chronic effects of MK on the ventricular remodeling after myocardial infarction (MI) remain to be confirmed. MI was created in Wistar rat by ligation of the left anterior discending coronary artery. Rats of MK overexpression were prepared by intramyocardial injection of adenoviruses encoding MK (AdMK, n=12) at the onset of MI. Control rats were injected with adenoviruses encoding beta-galactosidase (AdLacZ, n=12). In echocardiography 4w after MI, AdMK showed smaller LVESD and LVEDD than AdLacZ (LVESD: 6.7±0.7 vs. 9.3±0.7mm, LVEDD: 8.7±0.7 vs. 10.7±0.7mm, p<0.01). AdMK had better FS than AdLacZ (FS: 23.0±2.8 vs. 12.4±2.1%, p<0.01). Better preservation of systolic/diastolic function in AdMK than AdLacZ was also recognized in the LV catheterization 6w after MI (dP/dtmax: 3092±619 vs. 2171±763mmHg/s, dP/dtmin: −2525±878 vs. −1700±722mmHg/s, LVEDP: 3.3±0.9 vs. 8.3±2.2mmHg, p<0.01). Morphological study on AdMK 6w after MI revealed less fibrosis (collagen deposition area: 10.2±5.3 vs. 15.3±4.5%, p<0.05) and a higher vWF-positive capillary density in the perinfarct zone (32±11 vs. 21±5/mm2, p<0.01) compared with AdLacZ. In Western blotting, the levels of Akt and ERK phosphorylation and PI3K were elevated in AdMK compared with AdLacZ (pAkt; 2.08-fold increase, pERK; 1.43-fold increase, PI3K; 2.36-fold increase, relative to AdLacZ, p<0.05). In addition, the level of Bcl-2 increased and the level of Bax decreased in AdMK compared with AdLacZ (Bcl-2; 2.15-fold increase, Bax; 3.63-fold decrease, relative to AdLacZ, p<0.01). Overexpression of MK has long-term beneficial effects to reduce the progression of LV remodeling and dysfunction after MI. This amelioration is attributable in part to an enhancement of neovascularization via PI3K/Akt and ERK pathways, and in part to anti-apoptotic actions regulating Bcl-2 and Bax. MK gene transfer might be a new therapeutic strategy for treatment of ischemic heart disease.