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Early treatment with hepatocyte growth factor improves cardiac function in experimental heart failure induced by
Hongkui Jin1, Renhui Yang, Wei Li
1Department of Cardiovascular Research, Genentech, Inc., South San Francisco, California 94080, USA. hkj@gene.com
Insights
Hepatocyte growth factor (HGF) treatment improved cardiac function in rats after myocardial infarction (MI). HGF therapy helped restore heart performance, suggesting a potential benefit for ischemic cardiomyopathy.
Area of Science:
- Cardiovascular Research
- Regenerative Medicine
- Molecular Cardiology
Background:
- Plasma hepatocyte growth factor (HGF) increases rapidly after cardiac ischemia/reperfusion, showing acute cardioprotective effects.
- Sustained myocardial HGF expression post-myocardial infarction (MI) suggests a role in mitigating progression to heart failure.
Purpose of the Study:
- To investigate if HGF administration during endogenous HGF induction improves long-term cardiac function in rats with MI.
- To assess the therapeutic potential of HGF in established ischemic cardiomyopathy.
Main Methods:
- Myocardial infarction (MI) induced by 2-hour left coronary artery occlusion followed by reperfusion in rats.
- Intravenous HGF infusion (0.45 mg/kg/day for 6 days) initiated one day post-surgery.
- Cardiac function and hemodynamics assessed 8 weeks post-MI using catheters and flow probes in conscious animals.
Main Results:
- No significant difference in infarct size between HGF-treated and vehicle-treated groups (approx. 30% of left ventricle).
- Vehicle-treated MI rats exhibited heart failure signs: reduced cardiac index and stroke volume index, increased systemic vascular resistance.
- HGF treatment significantly improved cardiac index and stroke volume index, and reduced systemic vascular resistance, nearing levels of sham-operated controls.
Conclusions:
- HGF administration improves cardiac function and hemodynamics in a rat model of ischemic cardiomyopathy.
- HGF shows potential as a therapeutic agent for long-term cardiovascular benefit following myocardial infarction.
- Targeting endogenous HGF pathways may offer a strategy to combat heart failure progression after ischemic injury.
Abstract:
Plasma levels of hepatocyte growth factor (HGF) are increased within hours of cardiac ischemia/reperfusion in rats, and HGF has been shown to be cardioprotective toward acute ischemic injury. Myocardial levels of HGF mRNA and protein are increased for several days after myocardial infarction (MI), however, indicating a possible additional protective effect of HGF toward the progression of MI to heart failure. The purpose of this study was to determine whether HGF administration during the time course of endogenous cardiac HGF induction would lead to long-term improvement in cardiac function in rats with MI. MI was induced by 2-h occlusion of the left coronary artery, followed by reperfusion. HGF was given by intravenous infusion at 0.45 mg/kg/day for 6 days beginning on the day after surgery. Cardiac function and hemodynamic parameters were measured by using indwelling catheters and perivascular flow probes in conscious animals 8 weeks post-MI. Myocardial infarcts were approximately 30% of the left ventricle, and there was no difference in infarct size between the vehicle-treated and HGF-treated groups. Compared with untreated sham-operated rats, vehicle-treated MI animals had significantly lower cardiac index and stroke volume index and higher systemic vascular resistance, indicating heart failure developed. Treatment with HGF caused a significant increase in cardiac index and stroke volume index and a reduction in systemic vascular resistance in rats with MI, restoring these parameters close to those observed in sham-operated control animals. These results provide direct evidence that HGF may be of benefit to cardiovascular function in ischemic cardiomyopathy.