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

Abstract

Hepatocyte growth factor (HGF) reportedly exerts beneficial effects on the heart following myocardial infarction and during nonischemic cardiomyopathy, but the precise mechanisms underlying the latter have not been well elucidated. We generated nonischemic cardiomyopathy in mice by injecting them with doxorubicin (15 mg/kg ip). Two weeks later, when cardiac dysfunction was apparent, an adenoviral vector encoding human HGF gene (Ad.CAG-HGF, 1×1011 particles/mouse) was injected into the hindlimb muscles; LacZ gene served as the control. Left ventricular dilatation and dysfunction normally seen 4 wk after doxorubicin administration were significantly mitigated in HGF-treated mice, as were the associated cardiomyocyte atrophy/degeneration and myocardial fibrosis. Myocardial expression of GATA-4 and a sarcomeric protein, myosin heavy chain, was downregulated by doxorubicin, but the expression of both was restored by HGF treatment. The protective effect of HGF against doxorubicin-induced cardiomyocyte atrophy was confirmed in an in vitro experiment, which also showed that neither cardiomyocyte apoptosis nor proliferation plays significant roles in the present model. Upregulation of c-Met/HGF receptor was noted in HGF-treated hearts. Among the mediators downstream of c-Met, the activation of extracellular signal-regulated kinase (ERK) was reduced by doxorubicin, but the activity was restored by HGF. Levels of transforming growth factor-β1 and cyclooxygenase-2 did not differ between the groups. Our findings suggest the HGF gene delivery exerts therapeutic antiatrophic/degenerative and antifibrotic effects on myocardium in cases of established cardiac dysfunction caused by doxorubicin. These beneficial effects appear to be related to HGF-induced ERK activation and upregulation of c-Met, GATA-4, and sarcomeric proteins.

Sexual Dimorphism of Doxorubicin-Mediated Cardiotoxicity

“…[20][21][22] Females had an almost preserved LVEF, whereas males had a severe decrease in LVEF combined with pulmonary edema, ascites, structural myocardial alterations including myolysis and fibrosis and high levels of Il-6, Anf, and Mcip1 mRNA, which have all been correlated with the severity of left ventricular dysfunction. 23,24 Thus, females are better protected from doxorubicin-induced heart failure.…”

Heparin-binding epidermal growth factor-like growth factor and hepatocyte growth factor inhibit cholestatic liver injury in mice through different mechanisms

“…Moreover, combination therapy may be more beneficial based on the greater anticholestatic and regenerative activities observed in hepatocytes during the chronic phase. This study used an in vivo adenoviral gene transduction strategy to investigate whether HB-EGF has the potential to be used as a therapeutic agent for diverse hepatic disorders, particularly those with complex pathogenesis, including hepatocyte necrosis, liver fibrosis, and cholestatic liver injuries, as well as the differences in the therapeutic actions and pathophysiologic roles of HB-EGF and HGF (20,29,35,40,54,55). Future preclinical studies should examine long-term effectiveness and optimize pharmacotherapeutic protocols for each liver disease, including the timing of growth factor administration, the effects of gene vs. protein therapy, clinically appropriate vectors, and any treatment-related adverse effects, including the potential for hepatocarcinogenesis.…”

HGF/Met Axis in Heart Function and Cardioprotection

“…The anti-fibrotic action of HGF occurs via a mechanism involving production of NO in doxorubicin-mediated cardiac damage [52]. Inhibition of NO production leads to the up-regulation of ACE [53] and accelerates fibrosis [54].…”