Protective Roles of Endothelial AMP-Activated Protein Kinase Against Hypoxia-Induced Pulmonary Hypertension in Mice.

RATIONALE: Endothelial AMP-activated protein kinase (AMPK) plays an important role for vascular homeostasis, and its role is impaired by vascular inflammation. However, the role of endothelial AMPK in the pathogenesis of pulmonary arterial hypertension (PAH) remains to be elucidated. OBJECTIVE: To determine the role of endothelial AMPK in the development of PAH. METHODS AND RESULTS: Immunostaining showed that endothelial AMPK is downregulated in the pulmonary arteries of patients with PAH and hypoxia mouse model of pulmonary hypertension (PH). To elucidate the role of endothelial AMPK in PH, we used endothelial-specific AMPK-knockout mice (eAMPK(-/-)), which were exposed to hypoxia. Under normoxic condition, eAMPK(-/-) mice showed the normal morphology of pulmonary arteries compared with littermate controls (eAMPK(flox/flox)). In contrast, development of hypoxia-induced PH was accelerated in eAMPK(-/-) mice compared with controls. Furthermore, the exacerbation of PH in eAMPK(-/-) mice was accompanied by reduced endothelial function, upregulation of growth factors, and increased proliferation of pulmonary artery smooth muscle cells. Importantly, conditioned medium from endothelial cells promoted pulmonary artery smooth muscle cell proliferation, which was further enhanced by the treatment with AMPK inhibitor. Serum levels of inflammatory cytokines, including tumor necrosis factor-α and interferon-γ were significantly increased in patients with PAH compared with healthy controls. Consistently, endothelial AMPK and cell proliferation were significantly reduced by the treatment with serum from patients with PAH compared with controls. Importantly, long-term treatment with metformin, an AMPK activator, significantly attenuated hypoxia-induced PH in mice. CONCLUSIONS: These results indicate that endothelial AMPK is a novel therapeutic target for the treatment of PAH.

Basigin Promotes Cardiac Fibrosis and Failure in Response to Chronic Pressure Overload in Mice.

OBJECTIVE: Basigin (Bsg) is a transmembrane glycoprotein that activates matrix metalloproteinases and promotes inflammation. However, the role of Bsg in the pathogenesis of cardiac hypertrophy and failure remains to be elucidated. We examined the role of Bsg in cardiac hypertrophy and failure in mice and humans. APPROACH AND RESULTS: We performed transverse aortic constriction in Bsg(+/-) and in wild-type mice. Bsg(+/-) mice showed significantly less heart and lung weight and cardiac interstitial fibrosis compared with littermate controls after transverse aortic constriction. Both matrix metalloproteinase activities and oxidative stress in loaded left ventricle were significantly less in Bsg(+/-) mice compared with controls. Echocardiography showed that Bsg(+/-) mice showed less hypertrophy, less left ventricular dilatation, and preserved left ventricular fractional shortening compared with littermate controls after transverse aortic constriction. Consistently, Bsg(+/-) mice showed a significantly improved long-term survival after transverse aortic constriction compared with Bsg(+/+) mice, regardless of the source of bone marrow (Bsg(+/+) or Bsg(+/-)). Conversely, cardiac-specific Bsg-overexpressing mice showed significantly poor survival compared with littermate controls. Next, we isolated cardiac fibroblasts and examined their responses to angiotensin II or mechanical stretch. Both stimuli significantly increased Bsg expression, cytokines/chemokines secretion, and extracellular signal-regulated kinase/Akt/JNK activities in Bsg(+/+) cardiac fibroblasts, all of which were significantly less in Bsg(+/-) cardiac fibroblasts. Consistently, extracellular and intracellular Bsg significantly promoted cardiac fibroblast proliferation. Finally, serum levels of Bsg were significantly elevated in patients with heart failure and predicted poor prognosis. CONCLUSIONS: These results indicate the crucial roles of intracellular and extracellular Bsg in the pathogenesis of cardiac hypertrophy, fibrosis, and failure in mice and humans.

Usefulness of anterior chamber depth measurement for efficacy assessment of steroid pulse therapy in patients with Vogt-Koyanagi-Harada disease.

PURPOSE: To clarify the usefulness of measuring anterior chamber depth by the IOLMaster for early-stage assessment of the therapeutic effect of steroid pulse therapy in patients with Vogt-Koyanagi-Harada (VKH) syndrome with active uveitis. METHODS: Seven patients with VKH syndrome (three men and four women) participated in the study (14 eyes). All patients had exudative retinal detachment in addition to iritis, and received steroid pulse therapy: infusion of methylprednisolone (1000 mg × 3 days) followed by tapering oral administration of prednisolone (40, 30, 20, 15, 10, and 5 mg/day) over a week. Corrected visual acuity, manifest spherical equivalent, anterior chamber flare, axial length, and anterior chamber depth were measured before and after the pulse therapy. Anterior chamber flare was measured using a laser flare-cell meter, and axial length and anterior chamber depth were measured using the IOLMaster. RESULTS: After 1 week of steroid pulse therapy, anterior chamber depth significantly increased from the initial value of 2.94 ± 0.34 mm to 3.12 ± 0.38 mm (Wilcoxon signed-rank test, P = 0.002). After 1 month of steroid pulse therapy, significant changes were observed in corrected visual acuity (P = 0.01), manifest spherical equivalent (P = 0.002), anterior chamber flare (P = 0.03), axial length (P = 0.02), and anterior chamber depth (P = 0.002). CONCLUSION: Measurement of anterior chamber depth using the IOLMaster is useful for early-stage assessment of the effect of steroid pulse therapy in patients with VKH syndrome who develop active uveitis. Change in anterior chamber depth is the most sensitive indicator of inflammatory activity in patients with this syndrome.