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Endothelial PGC-1? mediates vascular dysfunction in diabetes.

ABSTRACT: Endothelial dysfunction is a central hallmark of diabetes. The transcriptional coactivator PGC-1? is a powerful regulator of metabolism, but its role in endothelial cells remains poorly understood. We show here that endothelial PGC-1? expression is high in diabetic rodents and humans and that PGC-1? powerfully blocks endothelial migration in cell culture and vasculogenesis in vivo. Mechanistically, PGC-1? induces Notch signaling, blunts activation of Rac/Akt/eNOS signaling, and renders endothelial cells unresponsive to established angiogenic factors. Transgenic overexpression of PGC-1? in the endothelium mimics multiple diabetic phenotypes, including aberrant re-endothelialization after carotid injury, blunted wound healing, and reduced blood flow recovery after hindlimb ischemia. Conversely, deletion of endothelial PGC-1? rescues the blunted wound healing and recovery from hindlimb ischemia seen in type 1 and type 2 diabetes. Endothelial PGC-1? thus potently inhibits endothelial function and angiogenesis, and induction of endothelial PGC-1? contributes to multiple aspects of vascular dysfunction in diabetes.

SUBMITTER: Sawada N

PROVIDER: S-EPMC4040246 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Endothelial PGC-1α mediates vascular dysfunction in diabetes.

Sawada Naoki N Jiang Aihua A Takizawa Fumihiko F Safdar Adeel A Manika Andre A Tesmenitsky Yevgenia Y Kang Kyu-Tae KT Bischoff Joyce J Kalwa Hermann H Sartoretto Juliano L JL Kamei Yasutomi Y Benjamin Laura E LE Watada Hirotaka H Ogawa Yoshihiro Y Higashikuni Yasutomi Y Kessinger Chase W CW Jaffer Farouc A FA Michel Thomas T Sata Masataka M Croce Kevin K Tanaka Rica R Arany Zolt Z

Cell metabolism 20140201 2

Endothelial dysfunction is a central hallmark of diabetes. The transcriptional coactivator PGC-1α is a powerful regulator of metabolism, but its role in endothelial cells remains poorly understood. We show here that endothelial PGC-1α expression is high in diabetic rodents and humans and that PGC-1α powerfully blocks endothelial migration in cell culture and vasculogenesis in vivo. Mechanistically, PGC-1α induces Notch signaling, blunts activation of Rac/Akt/eNOS signaling, and renders endotheli ...[more]

PMID: 24506866

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Project description:BackgroundThe airway epithelial barrier function is disrupted in the airways of asthmatic patients. Abnormal mitochondrial biogenesis is reportedly involved in the pathogenesis of asthma. However, the role of mitochondrial biogenesis in the airway barrier dysfunction has not been elucidated yet. This study aimed to clarify whether the peroxisome proliferator-activated receptor γ coactivator-1alpha (PGC-1α), a central regulator of mitochondrial biogenesis, is involved in the disruption of the airway barrier function induced by aeroallergens.MethodsBEAS-2B cells were exposed to house dust mite (HDM) and the expressions of PGC-1α and E-cadherin, a junctional protein, were examined by immunoblotting. The effect of SRT1720, a PGC-1α activator, was investigated by immunoblotting, immunocytochemistry, and measuring the transepithelial electrical resistance (TEER) on the HDM-induced reduction in mitochondrial biogenesis markers and junctional proteins in airway bronchial epithelial cells. Furthermore,the effects of protease activated receptor 2 (PAR2) inhibitor, GB83, Toll-like receptor 4 (TLR4) inhibitor, lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS), protease inhibitors including E64 and 4-(2-Aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF) on the HDM-induced barrier dysfunction were investigated.ResultsThe amounts of PGC-1α and E-cadherin in the HDM-treated cells were significantly decreased compared to the vehicle-treated cells. SRT1720 restored the expressions of PGC-1α and E-cadherin reduced by HDM in BEAS-2B cells. Treatment with SRT1720 also significantly ameliorated the HDM-induced reduction in TEER. In addition, GB83, LPS-RS, E64 and AEBSF prevented the HDM-induced reduction in the expression of PGC1α and E-cadherin.ConclusionsThe current study demonstrated that HDM disrupted the airway barrier function through the PAR2/TLR4/PGC-1α-dependent pathway. The modulation of this pathway could be a new approach for the treatment of asthma.

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Endothelial PGC-1? mediates vascular dysfunction in diabetes.

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Endothelial PGC-1α mediates vascular dysfunction in diabetes.

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