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Hexarelin treatment in male ghrelin knockout mice after myocardial infarction
Yuanjie Mao1, Takeshi Tokudome, Ichiro Kishimoto
1Department of Biochemistry, National Cardiovascular Center Research Institute, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan. kishimot@hsp.ncvc.go.jp.
Insights
Hexarelin treatment improved heart function after myocardial infarction in ghrelin-knockout mice, showing greater efficacy than ghrelin in enhancing cardiac performance and reducing mortality.
Area of Science:
- Cardiovascular Biology
- Endocrinology
- Pharmacology
Background:
- Ghrelin and hexarelin exhibit cardioprotective effects via distinct receptors.
- The comparative efficacy of hexarelin and ghrelin post-myocardial infarction (MI) in vivo remains unelucidated.
- Ghrelin deficiency exacerbates cardiac dysfunction following MI.
Purpose of the Study:
- To determine if hexarelin can mitigate cardiac deficits in ghrelin-deficient mice.
- To compare the therapeutic effects of hexarelin and ghrelin in a mouse model of acute myocardial infarction.
- To assess the impact of hexarelin and ghrelin on cardiac function, mortality, and autonomic activity post-MI.
Main Methods:
- Male ghrelin-knockout mice underwent induced myocardial infarction via left coronary artery ligation.
- Mice received subcutaneous treatment with hexarelin, ghrelin, or vehicle for two weeks.
- Cardiac function, mortality rates, and heart rate variability were analyzed post-treatment.
Main Results:
- Hexarelin and ghrelin treatments significantly reduced 2-week mortality compared to vehicle (6.7% and 14.3% vs. 50%, respectively).
- Both treatments improved cardiac output, ejection fraction, and diastolic function (dP/dt min) compared to controls.
- Hexarelin demonstrated superior efficacy over ghrelin in improving ejection fraction, dP/dt max, and dP/dt min.
Conclusions:
- Hexarelin treatment effectively compensates for ghrelin deficiency and enhances cardiac recovery post-myocardial infarction.
- Hexarelin exhibits greater cardioprotective benefits than ghrelin in ghrelin-knockout mice following MI.
- Both hexarelin and ghrelin suppress sympathetic nervous activity and reduce mortality, but hexarelin offers superior functional recovery.
Abstract:
Both ghrelin and the synthetic analog hexarelin are reported to possess cardioprotective actions that are mainly exerted through different receptors. However, their effects on acute myocardial infarction have not been compared in vivo. This study aimed to clarify whether hexarelin treatment can compensate for ghrelin deficiency in ghrelin-knockout mice and to compare the effects of hexarelin (400 nmol/kg/d, sc) and equimolar ghrelin treatment after myocardial infarction. Myocardial infarction was produced by left coronary artery ligation in male ghrelin-knockout mice, which then received ghrelin, hexarelin, or vehicle treatment for 2 weeks. The mortality within 2 weeks was significantly lower in the hexarelin group (6.7%) and ghrelin group (14.3%) than in the vehicle group (50%) (P < .05). A comparison of cardiac function 2 weeks after infarction showed that in the ghrelin and hexarelin treatment groups, cardiac output was greater, whereas systolic function, represented by ejection fraction, and diastolic function, represented by dP/dt min (peak rate of pressure decline), were significantly superior compared with the vehicle group (P < .05). Hexarelin treatment was more effective than ghrelin treatment, as indicated by the ejection fraction, dP/dt max (peak rate of pressure rise), and dP/dt min. Telemetry recording and heart rate variability analysis demonstrated that sympathetic nervous activity was clearly suppressed in the hexarelin and ghrelin groups relative to the vehicle group. Our data demonstrated that hexarelin treatment can result in better heart function than ghrelin treatment 2 weeks after myocardial infarction in ghrelin-knockout mice, although both hormones have similar effects on heart rate variability and mortality.