Patients with ischemic heart disease or chronic heart failure show altered levels of obestatin, suggesting a role for this peptide in human heart function. We have previously demonstrated that GH secretagogues and the ghrelin gene-derived peptides, including obestatin, exert cardiovascular effects by modulating cardiac inotropism and vascular tone, and reducing cell death and contractile dysfunction in hearts subjected to ischemia/reperfusion (I/R), through the Akt/nitric oxide (NO) pathway. However, the mechanisms underlying the cardiac actions of obestatin remain largely unknown. Thus, we hypothesized that obestatin-induced activation of PI3K/Akt/NO and PKG signaling is implicated in protection of the myocardium when challenged by adrenergic, endothelinergic or I/R stress. We show that obestatin exerts an inhibitory tone on the performance of rat papillary muscle in both basal conditions and under β-adrenergic overstimulation, through endothelial-dependent NO/cGMP/PKG signaling. This pathway was also involved in the vasodilator effect of the peptide, used both alone and under stress induced by endothelin-1. Moreover, when infused during early reperfusion, obestatin reduced infarct size in isolated I/R rat hearts, through an NO/PKG pathway, comprising ROS/PKC signaling, and converging on mitochondrial ATP-sensitive potassium [mitoK(ATP)] channels. Overall, our results suggest that obestatin regulates cardiovascular function in stress conditions and induces cardioprotection by mechanisms dependent on activation of an NO/soluble guanylate cyclase (sGC)/PKG pathway. In fact, obestatin counteracts exaggerated β-adrenergic and endothelin-1 activity, relevant factors in heart failure, suggesting multiple positive effects of the peptide, including the lowering of cardiac afterload, thus representing a potential candidate in pharmacological postconditioning.

Obestatin regulates cardiovascular function and promotes cardioprotection through the nitric oxide pathway

PENNA, Claudia
Co-first
;
TULLIO, FRANCESCA;FEMMINÒ, SAVERIA;CERRA, MARIA CARMELA;GALLO, Maria Pia;GESMUNDO, IACOPO;FANCIULLI, ALESSANDRO;BRIZZI, Maria Felice
;
PAGLIARO, Pasquale;ALLOATTI, Giuseppe;GRANATA, Riccarda
Co-last
2017-01-01

Abstract

Patients with ischemic heart disease or chronic heart failure show altered levels of obestatin, suggesting a role for this peptide in human heart function. We have previously demonstrated that GH secretagogues and the ghrelin gene-derived peptides, including obestatin, exert cardiovascular effects by modulating cardiac inotropism and vascular tone, and reducing cell death and contractile dysfunction in hearts subjected to ischemia/reperfusion (I/R), through the Akt/nitric oxide (NO) pathway. However, the mechanisms underlying the cardiac actions of obestatin remain largely unknown. Thus, we hypothesized that obestatin-induced activation of PI3K/Akt/NO and PKG signaling is implicated in protection of the myocardium when challenged by adrenergic, endothelinergic or I/R stress. We show that obestatin exerts an inhibitory tone on the performance of rat papillary muscle in both basal conditions and under β-adrenergic overstimulation, through endothelial-dependent NO/cGMP/PKG signaling. This pathway was also involved in the vasodilator effect of the peptide, used both alone and under stress induced by endothelin-1. Moreover, when infused during early reperfusion, obestatin reduced infarct size in isolated I/R rat hearts, through an NO/PKG pathway, comprising ROS/PKC signaling, and converging on mitochondrial ATP-sensitive potassium [mitoK(ATP)] channels. Overall, our results suggest that obestatin regulates cardiovascular function in stress conditions and induces cardioprotection by mechanisms dependent on activation of an NO/soluble guanylate cyclase (sGC)/PKG pathway. In fact, obestatin counteracts exaggerated β-adrenergic and endothelin-1 activity, relevant factors in heart failure, suggesting multiple positive effects of the peptide, including the lowering of cardiac afterload, thus representing a potential candidate in pharmacological postconditioning.
2017
21
12
3670
3678
http://onlinelibrary.wiley.com/doi/10.1111/jcmm.13277/abstract?systemMessage=Wiley+Online+Library+usage+report+download+page+will+be+unavailable+on+Friday+24th+November+2017+at+21:00+EST+/+02.00+GMT+/+10:00+SGT+(Saturday+25th+Nov+for+SGT+
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5706590/
Penna, Claudia; Tullio, Francesca; Femminò, Saveria; Rocca, Carmine; Angelone, Tommaso; Cerra, MARIA CARMELA; Gallo, Maria Pia; Gesmundo, Iacopo; Fanc...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1641732
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