Postinfarction treatment with an adenoviral vector expressing hepatocyte growth factor relieves chronic left ventricular remodeling and dysfunction in mice

• Published in: Circulation (New York, N.Y.) N.Y.), 2003-05, Vol.107 (19), p.2499-2506
• Main Authors: YIWEN LI, TAKEMURA, Genzou, KAWASE, Yukinori, MARUYAMA, Rumi, OKADA, Hideshi, MINATOGUCHI, Shinya, MIZUGUCHI, Hiroyuki, FUJIWARA, Takako, FUJIWARA, Hisayoshi, KOSAI, Ken-Ichiro, YUGE, Kentaro, NAGANO, Satoshi, ESAKI, Masayasu, GOTO, Kazuko, TAKAHASHI, Tomoyuki, HAYAKAWA, Kenji, KODA, Masahiko
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; Animals; Biological and medical sciences; Bromodeoxyuridine; Cardiology. Vascular system; Cell Division - drug effects; Chronic Disease; Disease Models, Animal; Disease Progression; Genetic Vectors - genetics; Genetic Vectors - therapeutic use; Heart; Heart failure, cardiogenic pulmonary edema, cardiac enlargement; Hepatocyte Growth Factor - biosynthesis; Hepatocyte Growth Factor - genetics; Hepatocyte Growth Factor - pharmacology; Hepatocytes - drug effects; Humans; Immunohistochemistry; Male; Medical sciences; Mice; Mice, Inbred C57BL; Myocardial Infarction - pathology; Myocardial Infarction - physiopathology; Myocardial Infarction - therapy; Myocardium - pathology; Survival Rate; Time Factors; Transduction, Genetic - methods; Treatment Outcome; Ventricular Dysfunction, Left - drug therapy; Ventricular Dysfunction, Left - genetics; Ventricular Remodeling - drug effects; Ventricular Remodeling - genetics
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.0000065579.19126.B8

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. In mice, on day 3 after myocardial infarction (MI), adenovirus encoding human HGF (Ad.CAG-HGF) was injected into the hindlimb muscles (n=13). As a control (n=15), LacZ gene was used. A persistent increase in plasma human HGF was confirmed in the treated mice: 1.0+/-0.2 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 +/-dP/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. 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.