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    • Plasma apelin levels predict the major cardiovascular event

    2023-09-19

    Plasma apelin levels predict the major cardiovascular event after percutaneous coronary intervention in patients with ST elevation myocardial infarction (STEMI), and adverse events are higher in patients with lower plasma apelin levels [75]. Apelin and its receptor are markedly upregulated in the heart and skeletal muscle following myocardial injury or systemic hypoxic exposure through a hypoxia-inducible factor (HIF)-mediated pathway. Moreover, healthy-control rats exposed to hypoxic conditions also have exhibited elevated orexin of the apelin/apelin receptor signaling in myocardium, pulmonary circulation and skeletal muscle [76]. Under stressful conditions, plasma corticosterone levels and cardiac apelin expression are upregulated, thereby contributing to inhibition of stress-induced apoptosis in the heart [77]. In mice fed with a high-fat diet and subjected to myocardial I/R, apelin 13 administration significantly alleviated infarct size, myocardial apoptosis and mitochondrial damage (Table 1) [78]. Apelin gene therapy increases vascular density and alleviates diabetic cardiomyopathy by a mechanism involving activation of Sirt3 and upregulation of VEGF/VEGFR2 expression (Table 1) [79], [80]. These observations provide a novel mechanism with Sirt3 being essential for apelin-induced angiogenesis in diabetes following myocardial infarction [81]. Apelin-mediated protection against cardiac fibrosis results primarily from direct modulation of plasminogen activator inhibitor-1 gene expression, associated with synergistic inhibition of Ang II signaling and increased production of -NO (Fig. 2) [82]. In cultured primary cardiomyocytes under hypoxia/re-oxygenation, administration of apelin suppresses apoptosis and generation of reactive oxygen species. In addition, apelin improves cardiac dysfunction after myocardial I/R injury by inhibiting myocardial apoptosis and oxidative stress, along with upregulation of eNOS levels and of PI3K/Akt and activation of ERK1/2 phosphorylation signaling (Table 1 & Fig. 2) [83]. Genetic ablation of apelin leads to aggravated left ventricular injury following MI, while a synthetic apelin analogue, which mimics the function of apelin, markedly protects from myocardial I/R injury. This is accompanied by greater activation of survival pathways and promotion of angiogenesis (Table 1) [4]. Intracellular Ca abnormality and endoplasmic reticulum stress mediates cardiac dysfunction induced by myocardial I/R injury, and apelin 13 suppresses these pathogenic pathways [84], [85], [86]. The expression of apelin/apelin receptor in human endothelial cells is associated with shear stress, in which expression of apelin receptor is induced independently of its ligand apelin [87]. The recent findings broadened our view of the apelin/apelin receptor system by demonstrating that stretch-dependent apelin receptor signaling, rather than apelin receptor binding, contributed to increased cardiomyocyte cell size and myocardial hypertrophy [88]. Since the apelin receptor acts as a dual receptor for both mechanical stretch and endogenous apelin in cardiac hypertrophy, interventions targeting to balance these stimuli may determine the resulting adaptive physiology of apelin receptor [88].
    Role of apelin in vascular disease Apelin is an arterial and venous dilator in conscious rats [89], and acute apelin infusion causes peripheral and coronary vasodilatation with increased cardiac output without cardiac hypertrophy (Table 2) [42], [48]. This is attributed to stimulated NOS activity and expression (Table 2) [19], [90]. Apelin 13 can inhibit Ang II induced contractions by a nitric oxide-dependent mechanism on either endothelium intact or endothelium denuded rat portal vein rings [91]. In contrast, injection of pyr-apelin 13 (20 and 50nmol) intracerebroventricularly resulted in dose-dependent increases in mean arterial pressure and heart rate, suggesting that the peripheral and central actions of apelin can be distinct (Table 2) [92]. The NO signaling pathway is an important mechanism to regulate platelet activation which is known to contribute to thrombotic events leading to acute coronary syndromes and strokes [93], [94]. Apelin plays a critical role in the regulation of platelet activation. Apelin-deficient mice display a prothrombotic profile, suggesting a potential role of apelin in thrombotic disorders (Table 2) [93]. Tissue factor plays a pivotal role in the pathophysiology of acute coronary syndromes by triggering the formation of thrombi following endothelial injury. Apelin 13 functions as an active mediator in athero-thrombotic disease by suppressing the expression of tissue factor [95]. Thus, the development of promising strategies to interfere with Apelin/apelin receptor system and Apelin analogues might be a promising field for the therapeutic approach in thrombotic disease.