Adropin Is a Novel Regulator of Endothelial Function

Abstract

Background-Adropin is a recently identified protein that has been implicated in the maintenance of energy homeostasis and insulin resistance. Because vascular function and insulin sensitivity are closely related, we hypothesized that adropin may also exert direct effects on the endothelium. Methods and Results-In vitro cell culture models were partnered with an in vivo murine injury model to determine the potential vascular effects of adropin. Adropin was expressed in human umbilical vein and coronary artery endothelial cells (ECs). Adropin-treated endothelial cells exhibited greater proliferation, migration and capillary-like tube formation and less permeability and tumor necrosis factor-␣-induced apoptosis. In keeping with a vascular protective effect, adropin stimulated Akt Ser 473 and endothelial nitric oxide (NO) synthase Ser 1177 phosphorylation. The former was abrogated in the presence of the phosphatidylinositol 3-kinase inhibitor LY294002, whereas the latter was attenuated by LY294002 and by mitogen-activated protein kinase kinase 1 inhibition with PD98059. Together, these findings suggest that adropin regulates NO bioavailability and events via the phosphatidylinositol 3-kinase-Akt and extracellular signal regulated kinase 1/2 signaling pathways. Adropin markedly upregulated vascular endothelial growth factor receptor-2 (VEGFR2) transcript and protein levels, and in VEGFR2-silenced endothelial cells, adropin failed to induce phosphorylation of endothelial NO synthase, Akt, and extracellular signal regulated kinase 1/2, supporting VEGFR2 as an upstream target of adropin-mediated endothelial NO synthase activation. Last, adropin improved murine limb perfusion and elevated capillary density following induction of hindlimb ischemia. Conclusions-We report a potential endothelial protective role of adropin that is likely mediated via upregulation of endothelial NO synthase expression through the VEGFR2-phosphatidylinositol 3-kinase-Akt and VEGFR2-extracellular signal regulated kinase 1/2 pathways. Adropin represents a novel target to limit diseases characterized by endothelial dysfunction in addition to its favorable metabolic profile. (Circulation. 2010;122[suppl 1]:S185-S192.)Key Words: adropin Ⅲ angiogenesis Ⅲ endothelium Ⅲ nitric oxide T he endothelium plays a central role in the maintenance of vascular homeostasis, and impaired endothelial function contributes to the development and progression of diverse cardiovascular, inflammatory, metabolic, infectious, and renal diseases, of which atherothrombosis has the largest clinical impact. 1 Endothelial cell (EC) homeostasis is maintained in part through the synthesis of nitric oxide (NO), from the precursor L-arginine, under the influence of endothelial NO synthase (eNOS). Aside from exerting several critical antiinflammatory, antithrombotic, and antiatherosclerotic roles within blood vessels, NO also promotes postnatal angiogenesis and reparative vasculogenesis. Furthermore, there is good evidence that NO bioavailability serves an important role in metabol...

Dihydroartemisinin inhibits endothelial cell proliferation through the suppression of the ERK signaling pathway

“…Activation of the ERK signaling pathway increases cell growth, and numerous extracellular stimuli regulates endothelial cell proliferation through manipulation of this pathway (9). Pre-treatment with PD98059 reduces endothelial cell proliferation induced by adiponectin, ghrelin and adropin (37)(38)(39). The present results confirmed the role of ERK signaling in mediating DHA-induced inhibition of endothelial cell proliferation.…”

First and third trimester serum concentrations of adropin and copeptin in gestational diabetes mellitus and normal pregnancy

“…Adropin is encoded by the Energy Homeostasis Associated (Enho) gene that is widely expressed in the central nervous system, as well as peripheral tissues such as liver, the heart and skeletal muscles [14][15][16]. While the mechanism of release remains controversial, the rapid regulation according to energy and nutritional status has been observed.…”

Adropin: A New Marker for Predicting Late Saphenous Vein Graft Disease after Coronary Artery Bypass Grafting

“…Lovren et al [8] demonstrated that adropin could enhance the expression of endothelial nitric oxide synthase (eNOS) in the endothelium via activation of vascular endothelial growth factor receptor (EGFR) 2 phosphatidylinositol 3-kinase Akt and EGFR 2 extracellular signalregulated kinase 1/2 pathways. As eNOS is responsible for the production of vascular nitric oxide (NO) [13], adropin defi- Abbreviations: ACE = angiotensin-convertingenzym disease, CCB = calcium channel blocker, CCS = Can sure,SBP = systolic blood pressure and SVG = saphen me, ARB = angiotensin receptor block nadian Cardiovascular Society , CRP nous vein graft ker; BMI = body mass index, CAD = P = C-reactive protein, DBP = diastol = coronary artery olic blood presciency is associated with reduced nitric oxide bioavailability in the endothelium.…”

“…Adropin appears to participate in the maintenance of energy homeostasis and insulin response, which is closely related to the development and progression of atherogenesis [7]. A recent study found that adropin is also expressed in coronary artery endothelial cells and plays a potential endothelial protective role in mice [8]. It is well known that endothelial dysfunction is a key early event in atherogenesis and is integral in the onset of CAD and acute coronary syndromes (ACS) [9].…”