Abstract 3831: Growth-Hormone-Releasing-Hormone (GHRH) Agonist as a Potential Cardioprotective Agent in Rats With Post-Myocardial Infarction (MI)
Background Accumulating data support a cardioprotective role for the growth hormone (GH) axis. In addition, to GH itself and IGF-1, GH releasing peptides also exert a cardiac effect and GHRH mRNA is present in the heart. In order to test the hypothesis that GHRH exerts important cardioprotection we administered a potent GHRH agonist (JI-38) to rats following MI.
Methods MI was induced by coronary artery ligation in 6 month-old Fisher-344 rats. Animals were randomly assigned to receive: placebo (n=14), GHRH agonist (GHRH-A, n=8) and, rat recombinant GH (rGH, n=8) for 4 weeks. Cardiac function was assessed by echocardiography before and post-MI; histological sections were analyzed for capillary density and infarct size. Immunostaining of cardiomyocyte membrane was used to detect GHRH-receptor.
Results Body weight (BW) was similar in all treatment groups at baseline. In placebo group, MI significantly reduced BW from 225±4 to 208±3g (p<0.05), but GHRH-A group did not show such reduction (231±5 vs 225±3g). Conversely, rGH increased BW (217±4 vs 256±3g, p<0.01). Serum levels of GH (64±23 vs 52±12ng/ml) and IGF-1 (553±46 vs 502±36ng/ml) were similar in placebo and GHRH-A groups but in rGH group these levels were markedly increased (679±196 and 1052±91 ng/ml, p<0.01 vs placebo). A reduction in ejection fraction from 83±2 to 38±3% (p<0.05) due to MI was improved in GHRH-A (47±4%, p<0.05) but not in rGH group (44±2%, p=NS). Capillary density was higher in rGH (0.02±0.002/mm2, p<0.001) than in placebo or GHRH-A groups (0.01±0.001 and 0.006<0.001/mm2, respectively). Whereas, MI size in rGH and placebo groups was similar (45±2 vs 41±1%, respectively), GHRH-A rats had reduced MI size (36±3%, p<0.05 vs placebo and rGH). The presence of GHRH-receptor was confirmed by confocal microscopy.
Conclusions Thus treatment with a GHRH agonist, but not rGH, reduced infarct size and improved cardiac function by a direct myocardial action in the absence of increasing circulating GH or IGF-1 levels. The detection of GHRH-receptor on cardiomyocyte membranes supports the possibility of direct receptor activation of this pathway in the heart. GHRH agonists represent a potential novel therapeutic approach to attenuate impairment of cardiac function and left ventricular remodeling post-MI.