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    • Plasma apelin levels predict the major cardiovascular

    2024-05-03

    Plasma apelin levels predict the major cardiovascular event after percutaneous coronary intervention in patients with ST elevation myocardial infarction (STEMI), AZD1152-HQPA sale 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 AZD1152-HQPA sale 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.