Lebetin 2, a Snake Venom-Derived Natriuretic Peptide, Attenuates Acute Myocardial Ischemic Injury through the Modulation of Mitochondrial Permeability Transition Pore at the Time of Reperfusion

• Published in: PloS one Vol. 11; no. 9; p. e0162632
• Main Authors: Tourki, Bochra, Matéo, Philippe, Morand, Jessica, Elayeb, Mohamed, Godin-Ribuot, Diane, Marrakchi, Naziha, Belaidi, Elise, Messadi, Erij
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 12-09-2016; Public Library of Science (PLoS)
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Animals; Apoptosis; Biology and Life Sciences; Brain natriuretic peptide; Cardiotonic Agents - pharmacology; Channel opening; Cyclic GMP; Cyclic guanosine monophosphate; Extracellular signal-regulated kinase; Gangrene; Gene expression; Guanosine; Heart; Heart attack; Heart diseases; Heart failure; In Vitro Techniques; Injuries; Ischemia; Kinases; Laboratory animals; Male; Medicine and Health Sciences; Membrane permeability; Mitochondrial Membrane Transport Proteins - drug effects; Mitochondrial permeability transition pore; Muscle contraction; Myocardial infarction; Myocardial Infarction - pathology; Myocardial Reperfusion Injury - prevention & control; Myocardium; Natriuretic peptides; Peptides; Permeability; Phosphorylation; Physiology; Protein kinase C; Protein kinases; Proteins; Rats; Rats, Wistar; Receptors; Recovery; Reperfusion; Rodents; Signal Transduction; Signaling; Survival; Thoracic surgery; Venom; Venoms; Ventricle; Viper Venoms - pharmacology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0162632

Cardiac ischemia is one of the leading causes of death worldwide. It is now well established that natriuretic peptides can attenuate the development of irreversible ischemic injury during myocardial infarction. Lebetin 2 (L2) is a new discovered peptide isolated from Macrovipera lebetina venom with structural similarity to B-type natriuretic peptide (BNP). Our objectives were to define the acute cardioprotective actions of L2 in isolated Langendorff-perfused rat hearts after regional or global ischemia-reperfusion (IR). We studied infarct size, left ventricular contractile recovery, survival protein kinases and mitochondrial permeability transition pore (mPTP) opening in injured myocardium. L2 dosage was determined by preliminary experiments at its ability to induce cyclic guanosine monophosphate (cGMP) release without changing hemodynamic effects in normoxic hearts. L2 was found to be as effective as BNP in reducing infarct size after the induction of either regional or global IR. Both peptides equally improved contractile recovery after regional IR, but only L2 increased coronary flow and reduced severe contractile dysfunction after global ischemia. Cardioprotection afforded by L2 was abolished after isatin or 5-hydroxydecanote pretreatment suggesting the involvement of natriuretic peptide receptors and mitochondrial KATP (mitoKATP) channels in the L2-induced effects. L2 also increased survival protein expression in the reperfused myocardium as evidenced by phosphorylation of signaling pathways PKCε/ERK/GSK3β and PI3K/Akt/eNOS. IR induced mitochondrial pore opening, but this effect was markedly prevented by L2 treatment. These data show that L2 has strong cardioprotective effect in acute ischemia through stimulation of natriuretic peptide receptors. These beneficial effects are mediated, at least in part, by mitoKATP channel opening and downstream activated survival kinases, thus delaying mPTP opening and improving IR-induced mitochondrial dysfunction.