Atherosclerosis is a chronic lipid

Atherosclerosis is a chronic lipid metabolism disorder linked with lipid accumulation within the arterial wall and subsequent formation of foam cells and vascular disease [96], [97]. The level of apelin is decreased in human atherosclerotic coronary arteries [4], and coronary collateral formation in patients with stable NHS-12-Biotin correlates with higher plasma apelin levels [98]. Apelin 13 decreases lipid accumulation of foam cells and induces autophagy via activation of the PI3K/Beclin-1 pathway (Table 2) [99]. Apelin antagonizes Ang II-induced atherosclerosis and aneurysm in ApoE knockout mice by increasing NO production and suppressing neointimal formation and vascular remodeling (Table 2) [100]. Apelin null mice exhibit decreased smooth muscle positive area in the neointima compared with wild-type mice, while upregulation of the apelin/apelin receptor pathway promotes neointima formation in the carotid ligation model in mice (Table 2) [101]. Cell-based therapy using mesenchymal stem cells provides a promising approach for the management of peripheral arterial disease. Apelin facilitated mesenchymal stem cell-based therapy in peripheral arterial disease through promoting protective autophagy, accompanied with activation of AMPK and inhibition of mammalian target of rapamycin (mTOR) (Table 2 & Fig. 2) [102]. Increased pulmonary arterial pressure and vascular resistance are hallmarks of PAH, which contribute to right ventricular hypertrophy and failure [103]. Circulating levels of apelin and apelin expression are reduced in both pulmonary arterial endothelial cells (PAECs) and microvascular endothelial cells in patients with PAH (Table 2) [41], [104], [105]. Enhancing apelin action is a therapeutically viable option for PAH [106]. Deletion of apelin leads to worsened vascular remodeling associated with exacerbated pulmonary hypertension by decreased activation of AMPK and eNOS (Table 2 & Fig. 2) [107]. Chronic treatment with pyr-apelin 13 significantly prevented PAH-induced downregulation of apelin/apelin receptor and activation of vasoconstrictors (Table 2) [108]. Deletion of apelin in PAECs led to augmented apoptosis and elevated proliferation of pulmonary arterial SMC, while administration of apelin remarkably reversed PAH in mice by rescuing BMPR2 and PAECs dysfunction [41]. Exogenous apelin decreased the level of pulmonary arterial SMC autophagy, proliferation and migration under hypoxia via activation of the PI3K/Akt/mTOR signaling pathway (Table 2 & Fig. 2) [109]. Apelin dependent miRNA-fibroblast growth factor signaling is also essential for pulmonary vascular homeostasis [105]. Given the diverse function of apelin peptides in vascular homeostasis, measures targeting the enhancement of the apelin pathway may provide a basis for novel anti-hypertensive and anti-atherosclerotic therapies.
Targeting the apelin pathway as novel therapies for cardiovascular diseases
Conclusions
Disclosures
Transparency document
Acknowledgements JCZ was supported by the National Basic Research Program of China (2014CB542300), the National Major Research Plan Training Program (91339108), the National Natural Science Foundation of China (81370362 & 81170246), and Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant (20152509). We acknowledge the funding support from Canadian Institutes of Health Research (CIHR) and Alberta Innovates-Health Solutions (AI-HS) to GYO and JCV.
Introduction Apelin was first isolated from bovine stomach extracts as the endogenous ligand for the G-protein-coupled APJ receptor (Tatemoto et al., 1998). Within central nervous system (CNS), both apelin and APJ receptor mRNA are expressed widely in forebrain and brainstem structures including the paraventricular nucleus of the hypothalamus (PVN) (O'Carroll et al., 2003; Pope et al., 2012), subventricular organs (Dai et al., 2013) and rostral ventrolateral medulla (RVLM) (Zhang et al., 2009), nucleus tractus solitarius (NTS), dorsal motor nucleus of N.vagus (DMV) and hypoglossal nucleus (HGN) (Bulbul et al., 2018).