Disruption of the Apelin-APJ System Worsens Hypoxia-Induced Pulmonary Hypertension

Abstract

Objective The G-protein–coupled receptor APJ and its ligand apelin are highly expressed in the pulmonary vasculature, but their function in this vascular bed is unclear. We hypothesized that disruption of apelin signaling would lead to worsening of the vascular remodeling associated with pulmonary hypertension (PH). Methods and Results We found that apelin-null mice developed more severe PH compared with wild-type mice when exposed to chronic hypoxia. Microcomputed tomography of the pulmonary arteries demonstrated significant pruning of the microvasculature in the apelin-null mice. Apelin-null mice had a significant reduction of serum nitrate levels. This was secondary to downregulation of endothelial nitric oxide synthase (eNOS), which was associated with reduced expression of Kruppel-like factor 2, a known regulator of eNOS expression. In vitro knockdown studies targeting apelin in human pulmonary artery endothelial cells demonstrated decreased eNOS and Kruppel-like factor 2 expression, as well as impaired phosphorylation of AMP-activated kinase and eNOS. Moreover, serum apelin levels of patients with PH were significantly lower than those of controls. Conclusion These data demonstrate that disruption of apelin signaling can exacerbate PH mediated by decreased activation of AMP-activated kinase and eNOS, and they identify this pathway as a potentially important therapeutic target for treatment of this refractory human disease.

Disruption of PPARγ/β-catenin–mediated regulation of apelin impairs BMP-induced mouse and human pulmonary arterial EC survival

“…In addition to the autocrine functions of apelin, it displays a paracrine effect by attenuating the response of PASMCs to growth factors and by promoting apoptosis. These findings support the beneficial effect of apelin on cardiac function in rats with PAH (28), underscore the adverse impact of its loss on the severity of PAH (29), and make apelin an attractive pharmacological target for the treatment of PAH.…”

“…Circulating ape- lin levels are decreased in IPAH patients (27), and apelin administration improves RV function in the monocrotaline rat model of PAH (28). In addition, loss of apelin worsens hypoxia-induced pulmonary hypertension in association with decreased number and enhanced muscularization of peripheral arteries (29).…”

“…However, the phenotype of the apelin-KO mouse is far less severe that that of the APJ-KO mouse, which dies in embryonic life in association with cardiac defects (45), suggestive of additional APJ ligands or ligand-independent effects of the receptor. Apelindeficient mice have decreased myocardial contractility under stress (45) and retardation of retinal angiogenesis (46), as well as exaggerated pulmonary hypertension (29). The latter has been attributed to the induction of eNOS by apelin.…”

Adipokines and cardiovascular disease: A comprehensive review

“…Another benefitial effect of apelin may be mitigation of angiotensin-2 induced cardiac fibrosis 72 and ischemia induced apoptosis of cardiomycytes 73 . Patients with pulmonary arterial hypertension (PAH) have lower plasma levels and reduced apelin expression in lung endothelial cells 74 . Chronic therapy with apelin alleviates the pulmonary hypertension and increases the contractility of failing right ventricle in mice with pulmonary hypertension induced by monocrotalin and hypoxia 68 .…”

Apelin-13 stimulates angiogenesis by promoting cross-talk between AMP-activated protein kinase and Akt signaling in myocardial microvascular endothelial cells

“…Previous studies indicated that apelin-13 is able to regulate glucose and lipid metabolism (12,13) via the activation of AMPK signaling. The disruption of apelin-13 signaling can increase the hypoxia-induced pulmonary hypertension mediated by decreased activation of AMPK and endothelial nitric oxide synthase (eNOS) (14). In addition, as protein kinase Akt/protein kinase B (Akt) signaling participates in vascular homeostasis and angiogenesis (15,16), it can also phosphorylate eNOS (17), resulting in NO production and subsequently leading to the regulation of vasomotor responses.…”