• 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • br Conclusions br Acknowledgments This study was supported b


    Acknowledgments This study was supported by funds from the National Natural Science Foundation of China (NSFC 31360245, 31460258) and the Applied Basic Research Foundation of Yunnan Province of China (2011FZ111).
    Introduction Acute myocardial infarction is the undoubted cause of cardiovascular morbidity and mortality worldwide. Although percutaneous coronary intervention has been widely applied in clinical settings, myocardial I/R injury is often accompanied by adverse events such as ventricular fibrillation and heart failure [1]. It is generally accepted that the phenomenon of myocardial I/R injury is apparently multifactorial and includes disturbances in energy metabolism and mitochondrial dysfunction, oxidative stress, enhanced mitochondrial permeability transition pore, inflammation and intracellular Ca2+ overload [2]. All these factors jointly can lead to the death of cardiomyocytes due to initiation of apoptosis and necrosis [3]. Therefore, one of the objectives of experimental cardiology is to develop therapeutic strategies aimed at saving the myocardium from I/R injury and improving reperfusion therapy. Galanin, a 29 (30 in human) amino Sunitinib neuropeptide (G1, Table 1), is involved in a large range of different vital functions, including regulation of the cardiovascular system. It acts via binding to the GalR1-3 receptors coupled with G-protein, all of which are found in the heart [4]. In addition to the complete peptide, several truncated galanin fragments are also biologically active. We have recently shown that N-terminal fragments of galanin (2-11) and (2-15) G2 and G3, respectively can reduce experimental myocardial I/R injury [5], [6]. Both peptides increased cell viability, inhibited apoptosis and the formation of excessive reactive oxygen species in mitochondria in response to hypoxia-reoxygenation in cultured rat cardiomyoblast H9C2 cells. Postischemic infusion of galanin fragment (2-11) or (2-15) improved functional recovery, reduced cell membrane damage in perfused rat heart and enhanced restoration of myocardial metabolic state during reperfusion. These findings demonstrated a direct action of both peptides G2 and G3 on the heart damaged by ischemia and reperfusion. Pilot experiments showed that intravenous administration of peptide G2 or G3 attenuated myocardial reperfusion injury in rats in vivo. The beneficial effects of these N-terminal fragments of galanin are probably associated with activation of the GalR2 receptor, since both ligands have a poor affinity for the receptor subtypes GalR1 and GalR3 [4], [7]. GalR2 receptor signals through several classes of G-proteins and stimulates multiple intracellular pathways. Most commonly, GalR2 acts through Gαq/11. This signaling involves phospholipase C activation, which triggers the cleavage of intracellular phosphatidylinositol 4,5-bisphosphate into inositol 1,4,5-triphosphate and diacyl glycerol, a PKC activator [8], and mediates the release of Ca2+ into the cytoplasm from intracellular stores and opening Ca2+-dependent channels [9]. GalR2 is coupled to Gαo-type G-protein and stimulates MAPK activity in protein kinase C dependent, a pertussis toxin (Ptx)-sensitive fashion [9]. GalR2 is also proposed to activate ras homolog family member A via coupling to G12/13-type G-protein and enhance cell survival by suppressing caspase-3 and caspase-9 activity [10]. Interaction of GalR2 with Ptx-sensitive Gi/o proteins inhibits adenylyl cyclase activity and reduces the concentration of cAMP in the cytosol [11]. This results in inhibition of the phosphorylation of cyclic AMP-responsive element-binding protein (CREB) [12], which leads to decreased expression of peroxisome proliferative activated receptor γ coactivator 1α and uncoupling protein 1 [13]. Additionally, inhibiting CREB phosphorylation results in GLUT4 translocation from intracellular membrane compartments to plasma membranes to enhance glucose uptake [14].