br The pathogenesis of AD and the

The pathogenesis of AD and the targets of apelin
Alzheimer's drugs
Conclusions
Introduction APJ, first identified from a human genomic library in 1993, belongs to a member of seven trans-membrane G protein-coupled receptor family. Its amino Mometasone furoate sequence has 31% homology with that of the human angiotensin II (Ang II) type 1 receptor, but it cannot bind Ang II. Of note, APJ has no subtypes and is the only known receptor of apelin, an endogenous peptide extracted from bovine stomach in 1998. Apelin is produced as a 77 amino acid preproapelin which is cleaved by an angiotensin-converting enzyme to form several shorter C-terminal bioactive peptides, such as apelin-13, -16, -17, -19, -36 as well as the pyroglutamate form of apelin-13, [Pyr1]apelin-13 [1]. It has been suggested that apelin-13 and apelin-17 possess much stronger activity than apelin-36. Apelin and APJ constitute a signaling pathway and are widely expressed in various tissues, especially in the cardiovascular system including the heart, kidney and vessels [2]. Abundant evidence reveals that apelin/APJ pathway is a critical regulator of cardiovascular function [3], [4] and plays an important role in the occurrence and development of cardiovascular diseases including atherosclerosis, coronary heart disease (CAD), heart failure, hypertension, pulmonary arterial hypertension (PAH), myocardial ischemia–reperfusion injury (MIRI) and atrial fibrillation [5]. Targeting apelin/APJ axis is protective against these diseases, one of the major causes of death in the world [6]. Thus, we review the regulation, cellular signaling pathways and cardiovascular physiological actions of apelin/APJ system and explore its emerging pathogenetic significance and therapeutic potential in several major cardiovascular diseases.
Regulation of apelin and APJ expression The expression of apelin and APJ is regulated by multiple factors. Geurts et al. reported that endocannabinoid in combination with lipopolysaccharide markedly upregulate apelin and APJ mRNA expression in the adipose tissue of obese and diabetic mice [7]. Mechanistically, cannabinoid receptor, interleukin (IL)-1 and tumor necrosis factor-α (TNF-α) are involved in this effect [7]. Hypoxia induces apelin expression in human adipocytes through a hypoxia-inducible factor 1α (HIF-1α)-dependent mechanism [8], whereas reoxygenation after hypoxia decreases its expression in human endothelial cells by activating fatty acid transport protein [9]. Interestingly, hypoxia, TNF-α and Ang II significantly enhance the expression of APJ in HepG2 cells [10]. Ang II type 1 receptor can stimulate apelin and APJ secretion through the activation of phospholipase C (PLC)-β/inositol-1,4,5-trisphosphate (IP3)/Ca/protein kinase C (PKC)/MAPK kinase/extracellular signal-regulated protein kinase 1/2 (ERK1/2) and PLC-β/diacylglycerol (DAG)/PKC ways, whereas Ang II type 2 receptor can reduce apelin and APJ production through the inhibition of adenylyl cyclase/cAMP/PKA and guanylate cyclase/cGMP/PKG pathways in 3T3-L1 adipocytes, indicating a differentially regulatory manner of apelin/APJ expression by Ang II type 1 and 2 receptors [11]. Bone morphogenic proteins (BMPs) are a subgroup of the transforming growth factor-β (TGF-β) superfamily. Some BMPs such as BMP4, 7 and 9 have been shown to diminish apelin mRNA levels in endothelial cells by stimulating BMP receptor 2 and then increasing expression of Smad 7, a transcriptional repressor of apelin [12]. Obesity surgery-induced weight loss leads to a significant reduction in apelin expression in omental and subcutaneous adipose tissue, contributing to improved insulin sensitivity [13]. Additionally, preterm and term spontaneous labors downregulate apelin expression but have no effect on APJ expression in human primary amnion cells [14]. However, the involved mechanisms are unclear.
Apelin/APJ cellular signaling pathways