Limits...
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

Impact of GHRH agonists on myocardium infarct burden and scar thicknessA. Representative images of Masson-Trichrome staining showing reduced infarct size and presence of viable tissue in the scar area of the treated hearts. (B. Bar graphs correspond to scar thickness. All values represent means ± SEM (n = 4–6).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4496393&req=5

Figure 3: Impact of GHRH agonists on myocardium infarct burden and scar thicknessA. Representative images of Masson-Trichrome staining showing reduced infarct size and presence of viable tissue in the scar area of the treated hearts. (B. Bar graphs correspond to scar thickness. All values represent means ± SEM (n = 4–6).

Mentions: Infarct size was determined by morphometric measurements [29]. Our previous results [28] showed that size of the MI was substantially reduced by GHRH-agonists, JI-38 (42 ± 1%), MR-356 (37 ± 2.5%) and MR-409 (42 ± 2.4%) vs. placebo (49 ± 2%, p < 0.05 for all) confirming the agonists' cardioprotective effect. In addition, most of the hearts treated with GHRH analogs showed presence of viable myocardium in the scar area in contrast to the untreated hearts; in general, the average infarct wall thickness in the mid ventricle tended to be thicker than in the placebo group (Figure 3A and 3B).


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)

Impact of GHRH agonists on myocardium infarct burden and scar thicknessA. Representative images of Masson-Trichrome staining showing reduced infarct size and presence of viable tissue in the scar area of the treated hearts. (B. Bar graphs correspond to scar thickness. All values represent means ± SEM (n = 4–6).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Impact of GHRH agonists on myocardium infarct burden and scar thicknessA. Representative images of Masson-Trichrome staining showing reduced infarct size and presence of viable tissue in the scar area of the treated hearts. (B. Bar graphs correspond to scar thickness. All values represent means ± SEM (n = 4–6).
Mentions: Infarct size was determined by morphometric measurements [29]. Our previous results [28] showed that size of the MI was substantially reduced by GHRH-agonists, JI-38 (42 ± 1%), MR-356 (37 ± 2.5%) and MR-409 (42 ± 2.4%) vs. placebo (49 ± 2%, p < 0.05 for all) confirming the agonists' cardioprotective effect. In addition, most of the hearts treated with GHRH analogs showed presence of viable myocardium in the scar area in contrast to the untreated hearts; in general, the average infarct wall thickness in the mid ventricle tended to be thicker than in the placebo group (Figure 3A and 3B).

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