Postinfarction Treatment With an Adenoviral Vector Expressing Hepatocyte Growth Factor Relieves Chronic Left Ventricular Remodeling and Dysfunction in Mice

Abstract

Background-Hepatocyte growth factor (HGF) is implicated in tissue regeneration, angiogenesis, and antiapoptosis.However, its chronic effects are undetermined on postinfarction left ventricular (LV) remodeling and heart failure. Methods and Results-In mice, on day 3 after myocardial infarction (MI), adenovirus encoding human HGF (Ad.CAG-HGF) was injected into the hindlimb muscles (nϭ13). As a control (nϭ15), LacZ gene was used. A persistent increase in plasma human HGF was confirmed in the treated mice: 1.0Ϯ0.2 ng/mL 4 weeks later. At 4 weeks after MI, the HGF-treated mice showed improved LV remodeling and dysfunction compared with controls, as indicated by the smaller LV cavity and heart/body weight ratio, greater % fractional shortening and LV ϮdP/dt, and lower LV end-diastolic pressure. The cardiomyocytes near MI, including the papillary muscles and trabeculae, were greatly hypertrophied in the treated mice. The old infarct size was similar between the groups, but the infarct wall was thicker in the treated mice, where the density of noncardiomyocyte cells, including vessels, was greater. Fibrosis of the ventricular wall was significantly reduced in them. Examination of 10-day-old MI revealed no proliferation or apoptosis but showed augmented expression of c-Met/HGF receptor in cardiomyocytes near MI, whereas a greater proliferating activity and smaller apoptotic rate of granulation tissue cells in the HGF-treated hearts was observed compared with controls. Conclusions-Postinfarction HGF gene therapy improved LV remodeling and dysfunction through hypertrophy of cardiomyocytes, infarct wall thickening, preservation of vessels, and antifibrosis. These findings imply a novel therapeutic approach against postinfarction heart failure.

Long-term effects of hepatocyte growth factor gene therapy in rat myocardial infarct model

“…Some investigators attempted to explain this discrepancy to be a result of too late initiation of the therapy in the study of Miyagawa et al 26 because at 2 weeks after myocardial infarction, the infarct had already begun to change into a scar, although this possible explanation does not seem to match the positive observation in their HGF gene and stem cell combination group. 4,7 In the present study, we did not find statistically significant differences in LVEF and EDV between the treatment and control groups despite HGF gene therapy being initiated immediately after coronary ligation.…”

Adiponectin protects against the development of systolic dysfunction following myocardial infarction

“…Furthermore, analyses of autopsy samples reveals that patients with end-stage heart failure, due to ischemic, inflammatory or idiopathic dilated cardiomyopathy, exhibit diminished densities and irregular patterns of myocardial capillaries [37] Indeed, agents that promote angiogenesis have been shown to be beneficial for cardiac remodeling after chronic myocardial ischemia [38][39][40]. In this study, the greater impaired LV function in adiponectin KO mice was accompanied by greater reductions in capillary density, whereas adenovirusmediated overexpression of adiponectin maintained capillary density in the infarct border zone.…”

Treatment with an adenoviral vector encoding hepatocyte growth factor mitigates established cardiac dysfunction in doxorubicin-induced cardiomyopathy

“…The adenoviral vector plasmid pAd-HGF, which is comprised of the cytomegalovirus immediate early enhancer, a modified chicken ␤-actin promoter, rabbit ␤-globin polyA (CAG) and hHGF cDNA (Ad.CAG-HGF), was constructed using the in vitro ligation method described previously (18,21). Control Ad-LacZ (Ad.CAG-LacZ) was prepared as described previously (7).…”

“…hHGF levels in plasma and tissues (n ϭ 3 to 4/group) were measured using an ELISA kit (Institute of Immunology) as previously reported (18).…”

“…For instance, HGF protected cardiomyocytes from acute ischemic death during myocardial infarction (27,36), and it enhanced survival among cardiomyocytes subjected to oxidative stress (13,36). In addition to its beneficial effects on cardiomyocytes under acute stress, recent research has demonstrated that HGF also exerts beneficial effects on cardiac function in animal models of chronic heart diseases, including ischemic cardiomyopathy following old myocardial infarction and hereditary cardiomyopathy (18,28,34). In those cases, the main mechanisms appeared to be a hypertrophic effect on cardiomyocytes as well as angiogenic and antifibrotic actions.…”