Modified N-Terminal Fragments of Galanin: Cardioprotective Properties and Mechanisms of Action.

The design of new drugs for treatment of cardiovascular diseases based on endogenous peptide hormones is of undoubted interest and stimulates intensive experimental research. One of the approaches for development in this area is synthesis of the short bioactive peptides that mimic effects of the larger peptide molecules and have improved physicochemical characteristics. In recent years, it has been found that the N-terminal fragments of the neuropeptide galanin reduce metabolic and functional disorders in the experimental heart damage. The review presents literature data and generalized results of our own experiments on the effects of the full-size galanin and its chemically modified N-terminal fragments (2-11) and (2-15) on the heart in normal conditions and in modeling pathophysiological conditions in vitro and in vivo. It has been shown that the spectrum of the peptide actions on the damaged myocardium includes decrease in the necrotic death of cardiomyocytes, decrease in the damage of sarcolemma, improvement in the metabolic state of myocardium, decrease in the formation of reactive oxygen species (ROS) and lipid peroxidation (LPO) products. Mechanisms of the protective action of the modified galanin fragments associated with activation of the GalR2 receptor subtype and manifestation of antioxidant properties are discussed. The data summarized in the review indicate that the molecular design of pharmacological agonists of the GalR2 receptor is a promising approach, because they can serve as a basis for the development of cardioprotectors influencing processes of free radical oxidation and metabolic adaptation.

Signaling pathways of a structural analogue of apelin-12 involved in myocardial protection against ischemia/reperfusion injury.

Exogenously administered chemically modified apelin-12 (MA) has been shown to exhibit protective effects in myocardial ischemia/reperfusion (I/R) injury. They include reduction of ROS formation, cell death and cardiometabolic abnormalities. The aim of the present study was to explore the role of the underlying signaling mechanisms involved in cardioprotection afforded by MA. Isolated perfused working rat hearts subjected to global ischemia and anaesthetized rats in vivo exposed to LAD coronary artery occlusion were used. Myocardial infarct size, cell membrane damage, cardiac dysfunction and metabolic state of the heart were used as indices of I/R injury at the end of reperfusion. Administration of specific inhibitors of MEK1/2, PI3K, NO synthase (NOS) or the mitochondrial ATP-sensitive K(+) (mito KATP) channels (UO126, LY294002, L-NAME or 5-hydroxydecanoate, respectively) reduced protective efficacy of MA in both models of I/R injury. This was evidenced by abrogation of infarct size limitation, deterioration of cardiac function recovery, and attenuation of metabolic restoration and sarcolemmal integrity. An enhancement of functional and metabolic recovery in isolated reperfused hearts treated with MA was suppressed by U-73122, chelerythrine, amiloride or KB-R7943 (inhibitors of phospholipase С (PLC), protein kinase C (PKC), Na(+)/H(+) or Na(+)/Ca(2+) exchange, respectively). Additionally, co-infusion of MA with amiloride or L-NAME reduced the integrity of cell membranes at early reperfusion compared with the effect of peptide alone. In conclusion, cardioprotection with MA is mediated by signaling via PLC and survival kinases, PKC, PI3K, and MEK1/2, with activation of downstream targets, NOS and mito KATP channels, and the sarcolemmal Na(+)/H(+) and Na(+)/Ca(2+) exchangers.