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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

Expression of GHRH-R and GHRH mRNA in H9c2 cardiomyoblast cell lineThe PCR products of GHRH-R, GHRH and β-actin were detected at their expected sizes: at 110 bp, 195 bp and 133 bp, respectively. Abbreviations: Pit: rat pituitary, Car: H9c2 cells, NEC: no enzyme (reverse transcriptase) control, M: marker.
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Figure 1: Expression of GHRH-R and GHRH mRNA in H9c2 cardiomyoblast cell lineThe PCR products of GHRH-R, GHRH and β-actin were detected at their expected sizes: at 110 bp, 195 bp and 133 bp, respectively. Abbreviations: Pit: rat pituitary, Car: H9c2 cells, NEC: no enzyme (reverse transcriptase) control, M: marker.

Mentions: Reverse-transcribed mRNA from H9c2 cells and rat pituitary was subjected to RT-PCR. The amplicons for GHRH (195 bp), GHRH-R (110 bp), and β-actin (133 bp) were detected at their expected sizes (Figure 1).


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)

Expression of GHRH-R and GHRH mRNA in H9c2 cardiomyoblast cell lineThe PCR products of GHRH-R, GHRH and β-actin were detected at their expected sizes: at 110 bp, 195 bp and 133 bp, respectively. Abbreviations: Pit: rat pituitary, Car: H9c2 cells, NEC: no enzyme (reverse transcriptase) control, M: marker.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Expression of GHRH-R and GHRH mRNA in H9c2 cardiomyoblast cell lineThe PCR products of GHRH-R, GHRH and β-actin were detected at their expected sizes: at 110 bp, 195 bp and 133 bp, respectively. Abbreviations: Pit: rat pituitary, Car: H9c2 cells, NEC: no enzyme (reverse transcriptase) control, M: marker.
Mentions: Reverse-transcribed mRNA from H9c2 cells and rat pituitary was subjected to RT-PCR. The amplicons for GHRH (195 bp), GHRH-R (110 bp), and β-actin (133 bp) were detected at their expected sizes (Figure 1).

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