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

Abstract

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.

Snake Venom Peptides: Tools of Biodiscovery

“…However, lebetin 2 was found to be more potent than BNP in enhancing the coronary flow, improving contractile dysfunction of myocardium and surviving global IR. It was also suggested that L2 could be a strong drug candidate for acute myocardial ischemia [ 151 ].…”

Isatin, an endogenous nonpeptide biofactor: A review of its molecular targets, mechanisms of actions, and their biomedical implications

“…Isatin also inhibited ANP-induced relaxation of isolated rabbit carotid arteries [110], partially inhibited CNP-stimulated cGMP production by human corneal epithelium [111], and blocked intracellular calcium transient induced by BNP in cardiac sympathetic neurons [112]. Isatin completely blocked the ANP effect on hyperpolarizationactivated current in human atrial myocytes [113] and decreased changes in intracellular calcium of cardiac sympathetic neurons induced by BNP [114]. Since the effect of isatin was similar to that of a cGMP protein kinase inhibitor, RP-8-Br-PET-cGMP, it was concluded that BNP acted via the NPR-A-cGMP-PKG pathway [112].…”

“…Interestingly, isatin acted as an antagonist not only of naturally occurring natriuretic peptides but also of Lebetin 2 (L2); this recently discovered peptide isolated from Macrovipera lebetina venom shares structural similarity to the B‐type natriuretic peptide (BNP) . Isatin blocked cardioprotection by Lebetin 2 in Langendorff‐perfused rat hearts exposed to regional or global ischemia‐reperfusion .…”

Vipers of the Middle East: A Rich Source of Bioactive Molecules

“…Lebetin 2 (L2) has been recently found in Macrovipera lebetina venom. This peptide shows structural similarity to B-type natriuretic peptide (BNP), a cardioprotective hormone, and, therefore, displays cardioprotective properties by stimulating natriuretic peptide receptors in ischemia-reperfusion injuries in isolated Langendorff-perfused rat hearts [ 87 ].…”