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New therapeutic approach to heart failure due to myocardial infarction based on targeting growth hormone-releasing hormone receptor.

Kanashiro-Takeuchi RM, Szalontay L, Schally AV, Takeuchi LM, Popovics P, Jaszberenyi M, Vidaurre I, Zarandi M, Cai RZ, Block NL, Hare JM, Rick FG - Oncotarget (2015)

Bottom Line: GHRH agonists decreased calcium influx and significantly improved cell survival.One week post-MI, MR-409 significantly reduced plasma levels of IL-2, IL-6, IL-10 and TNF-α 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.

View Article: PubMed Central - PubMed

Affiliation: Interdisciplinary Stem Cell Institute, University of Miami, Miller School of Medicine, Miami, Florida, United States of America.

ABSTRACT

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-α 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 remodeling by regulating pathways involved in fibrosis, apoptosis and cardiac repair. Patients with cardiac dysfunction could benefit from treatment with novel GHRH agonists.

No MeSH data available.


Related in: MedlinePlus

Effect of GHRH agonists on cardiomyocyte turnover and cell proliferationImmunostaining analysis of c-kit expression A. and cardiomyocyte mitosis B. based on the nuclear expression of phospho-histone H3 (pH3). Bar graphs show expression of c-kit+ cells and pH3+ cells per mm2 (*p < 0.05 vs. placebo, n = 5–6), respectively. Representative confocal immunofluorescent images illustrating expression of c-kit (red), CD45 (green) and nuclei (DAPI, blue) on the top panel (Scale bar: 20 μm) and co-localization of pH3 (magenta) and myosin light chain (MLC, green) and nuclei (DAPI, blue) on the bottom panel (Scale bar: 10 μm).
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Figure 5: Effect of GHRH agonists on cardiomyocyte turnover and cell proliferationImmunostaining analysis of c-kit expression A. and cardiomyocyte mitosis B. based on the nuclear expression of phospho-histone H3 (pH3). Bar graphs show expression of c-kit+ cells and pH3+ cells per mm2 (*p < 0.05 vs. placebo, n = 5–6), respectively. Representative confocal immunofluorescent images illustrating expression of c-kit (red), CD45 (green) and nuclei (DAPI, blue) on the top panel (Scale bar: 20 μm) and co-localization of pH3 (magenta) and myosin light chain (MLC, green) and nuclei (DAPI, blue) on the bottom panel (Scale bar: 10 μm).

Mentions: Cardiomyocyte mitotic division and c-kit expression were assessed by immunofluorescence. Treatment with GHRH analogs increased the number of endogenous cardiac c-kit+ cells and the cellular mitotic division (mitotic marker pH3) in the myocardium (Figure 5A and 5B, respectively). Furthermore, an inverse correlation was identified between MI size and c-kit expression (p = 0.0084, r = −0.5471) and cardiomyocyte mitotic division (p = 0.0096, r = −0.5390).


New therapeutic approach to heart failure due to myocardial infarction based on targeting growth hormone-releasing hormone receptor.

Kanashiro-Takeuchi RM, Szalontay L, Schally AV, Takeuchi LM, Popovics P, Jaszberenyi M, Vidaurre I, Zarandi M, Cai RZ, Block NL, Hare JM, Rick FG - Oncotarget (2015)

Effect of GHRH agonists on cardiomyocyte turnover and cell proliferationImmunostaining analysis of c-kit expression A. and cardiomyocyte mitosis B. based on the nuclear expression of phospho-histone H3 (pH3). Bar graphs show expression of c-kit+ cells and pH3+ cells per mm2 (*p < 0.05 vs. placebo, n = 5–6), respectively. Representative confocal immunofluorescent images illustrating expression of c-kit (red), CD45 (green) and nuclei (DAPI, blue) on the top panel (Scale bar: 20 μm) and co-localization of pH3 (magenta) and myosin light chain (MLC, green) and nuclei (DAPI, blue) on the bottom panel (Scale bar: 10 μm).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496393&req=5

Figure 5: Effect of GHRH agonists on cardiomyocyte turnover and cell proliferationImmunostaining analysis of c-kit expression A. and cardiomyocyte mitosis B. based on the nuclear expression of phospho-histone H3 (pH3). Bar graphs show expression of c-kit+ cells and pH3+ cells per mm2 (*p < 0.05 vs. placebo, n = 5–6), respectively. Representative confocal immunofluorescent images illustrating expression of c-kit (red), CD45 (green) and nuclei (DAPI, blue) on the top panel (Scale bar: 20 μm) and co-localization of pH3 (magenta) and myosin light chain (MLC, green) and nuclei (DAPI, blue) on the bottom panel (Scale bar: 10 μm).
Mentions: Cardiomyocyte mitotic division and c-kit expression were assessed by immunofluorescence. Treatment with GHRH analogs increased the number of endogenous cardiac c-kit+ cells and the cellular mitotic division (mitotic marker pH3) in the myocardium (Figure 5A and 5B, respectively). Furthermore, an inverse correlation was identified between MI size and c-kit expression (p = 0.0084, r = −0.5471) and cardiomyocyte mitotic division (p = 0.0096, r = −0.5390).

Bottom Line: GHRH agonists decreased calcium influx and significantly improved cell survival.One week post-MI, MR-409 significantly reduced plasma levels of IL-2, IL-6, IL-10 and TNF-α 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.

View Article: PubMed Central - PubMed

Affiliation: Interdisciplinary Stem Cell Institute, University of Miami, Miller School of Medicine, Miami, Florida, United States of America.

ABSTRACT

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-α 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 remodeling by regulating pathways involved in fibrosis, apoptosis and cardiac repair. Patients with cardiac dysfunction could benefit from treatment with novel GHRH agonists.

No MeSH data available.


Related in: MedlinePlus