期刊
ONCOTARGET
卷 6, 期 12, 页码 9728-9739出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.3303
关键词
growth hormone-releasing hormone; myocardial infarction; heart failure; remodeling; cardioprotection
资金
- National Heart, Lung, and Blood Institute [R01 HL107110]
- Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development of the Miami VA Healthcare System
- Department of Pathology, Division of Hematology/Oncology, Miller School of Medicine University of Miami
- Department of Medicine, Division of Hematology/Oncology, Miller School of Medicine University of Miami
- Sylvester Comprehensive Cancer Center of the Miller School of Medicine University of Miami
- South Florida Veterans Affairs Foundation for Research and Education
- L. Austin Weeks Endowment for Urologic Research
- Wallace H. Coulter Foundation [SB26 MT66142E]
- Department of Medicine, Dresden, Germany
- Helmholtz Alliance ICEMED (Imaging and Curing Environmental Metabolic Diseases) through the Initiative and Networking Fund of the Helmholtz Association
- Urology Care Foundation Research Scholars Program
- American Urological Association (AUA) Southeastern Section
Background: We previously showed that growth hormone-releasing hormone (GHRH) agonists are cardioprotective following myocardial infarction (MI). Here, our aim was to evaluate the in vitro and in vivo activities of highly potent new GHRH agonists, and elucidate their mechanisms of action in promoting cardiac repair. Methods and Results: H9c2 cells were cultured in serum-free medium, mimicking nutritional deprivation. GHRH agonists decreased calcium influx and significantly improved cell survival. Rats with cardiac infarction were treated with GHRH agonists or placebo for four weeks. MI size was reduced by selected GHRH agonists (JI-38, MR-356, MR-409); this accompanied an increased number of cardiac c-kit(+) cells, cellular mitotic divisions, and vascular density. One week post-MI, MR-409 significantly reduced plasma levels of IL-2, IL-6, IL-10 and TNF-alpha compared to placebo. Gene expression studies revealed favorable outcomes of MR-409 treatment partially result from inhibitory activity on pro-apoptotic molecules and pro-fibrotic systems, and by elevation of bone morphogenetic proteins. Conclusions: Treatment with GHRH agonists appears to reduce the inflammatory responses post-MI and may consequently improve mechanisms of healing and cardiac remod-eling by regulating pathways involved in fibrosis, apoptosis and cardiac repair. Patients with cardiac dysfunction could benefit from treatment with novel GHRH agonists.
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