br Apelin The APJ receptor ligand apelin firstly in

Apelin The APJ receptor ligand apelin firstly in 1998 was segregated from bovine stomach tissue. Human preproapelin gene located on chromosome Xq25–26.1. The apelin preproproteins consist of 77 amino Argatroban residues that are cleaved into biologically active C-terminal fragments of various sizes. The apelin peptides, including 13 (65–77), 17 (61–77), and 36 (42–77) amino acids (Fig. 1), are all capable of binding to APJ (Lee et al., 2000a; Tatemoto et al., 1998). Among apelin isoforms, apelin-13 has the highest plasma concentration and plays the most significant role in neuroprotection (Cheng et al., 2012; Zhen et al., 2013). In humans, apelin mRNA are expressed in various parts of the central nervous system such as the hippocampus, thalamus, hypothalamus, the basal forebrain, frontal cortex, corpus callosum, amygdala, substantia nigra, pituitary, and the spinal cord, as well as in peripheral organs such as placenta, kidney, heart, lung, and mammary gland (Kleinz and Davenport, 2005). Early on, apelin was recognized as an effective factor in lowering blood pressure by increasing endothelial nitric oxide (eNO) (Tatemoto et al., 2001b). APJ receptor identified as a coreceptor for human immunodeficiency virus type 1. It has been demonstrated that apelin by binding to APJ can block virus entry into the cells expressing APJ (Cayabyab et al., 2000). Experimental studies indicated that apelin led to protection against heart I/R injury in rats (Zeng et al., 2009), reducing in left ventricular preload and afterload and improving of cardiac contractility in C57/Bl/6 mice (Ashley et al., 2005), and reducing of the infarct size and normalization of the impaired cardiac function in C57BL/6 J mice with myocardial infarction (Xu et al., 2017). In patients along with chronic heart failure, apelin treatment caused peripheral and coronary vasodilatation and augmented cardiac output (Japp et al., 2010). Also it has been shown that apelin-13 plays an important role in improvment of post myocardial infarction repair through myocardial progenitor cells elevation in the infarcted hearts (Li et al., 2012). It has been shown that apelin-13 administration in patients with type 2 diabetes improves insulin sensitivity (Gourdy et al., 2017). Intravenous injection of apelin in mice potentially lowered blood glucose through elevating of glucose utilization in skeletal muscle and adipose tissue, and on the other hand, in high fat diet C57Bl6/J mice with hyperinsulinemia, hyperglycemia and obesity, apelin injection restored glucose tolerance and increased glucose utilization in peripheral tissues (Dray et al., 2008). In obes mice, apelin injection decreased body weight, adiposity, and blood triglycerides and fatty acids (Castan-Laurell et al., 2011). In rats with renal I/R injury, Apelin-13 treatment blocked increasing of inflammatory mediators and transforming growth factor (TGF)-β1, as well as apoptosis and subsequently, normalized the injury induced renal dysfunction (Chen et al., 2015b). Apelin plays a key role in inducing angiogenesis in phatological conditions including myocardial infarction, ischemic stroke, critical limb ischemia, tumor, cirrhosis, obesity, diabetes and other related diseases (Wu et al., 2017). Apelin expression increased in variety of cancers and indicated that plays a role in the progression of various cancers including lung cancer, gastroesophageal cancer, colonic cancer, hepatocellular carcinoma, prostate cancer, endometrial cancer, oral squamous cell carcinoma and brain cancer (Yang et al., 2016a). Different functions of apelin in the CNS have been documented in various studies. ICV administration of apelin-13 in rats caused significantly increasing in drinking behavior and water intake and also elevated plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone and decreased plasma levels of prolactin, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) (Taheri et al., 2002). It has been revealed that apelin has a diuretic activity and play an crucial role in body fluid homeostasis control by regulation of arginine vasopressin (AVP) neurons activity and AVP release (De Mota et al., 2004). ICV administration of apelin in lactating rats inhibited the activity of magnocellular and parvocellular oxytocin neurons and subsequently, reduced the amount of milk ejected (Bodineau et al., 2011). It has been reported that apelin-13 with dopamine, NO and prostaglandins cooperation, involved in the regulation of behavioral, endocrine and homeostatic responses in the CNS (Jaszberenyi et al., 2004).