Endothelial PGC-1α mediates vascular dysfunction in diabetes

Naoki Sawada, Aihua Jiang, Fumihiko Takizawa, Adeel Safdar, Andre Manika, Yevgenia Tesmenitsky, Kyu Tae Kang, Joyce Bischoff, Hermann Kalwa, Juliano L. Sartoretto, Yasutomi Kamei, Laura E. Benjamin, Hirotaka Watada, Yoshihiro Ogawa, Yasutomi Higashikuni, Chase W. Kessinger, Farouc A. Jaffer, Thomas Michel, Masataka Sata, Kevin CroceRica Tanaka, Zolt Arany

研究成果: Contribution to journalArticle

86 引用 (Scopus)

抜粋

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 endothelial cells unresponsive to established angiogenic factors. Transgenic overexpression of PGC-1α 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-1α rescues the blunted wound healing and recovery from hindlimb ischemia seen in type 1 and type 2 diabetes. Endothelial PGC-1α thus potently inhibits endothelial function and angiogenesis, and induction of endothelial PGC-1α contributes to multiple aspects of vascular dysfunction in diabetes.

元の言語英語
ページ(範囲)246-258
ページ数13
ジャーナルCell metabolism
19
発行部数2
DOI
出版物ステータス出版済み - 2 4 2014
外部発表Yes

All Science Journal Classification (ASJC) codes

  • Physiology
  • Molecular Biology
  • Cell Biology

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    Sawada, N., Jiang, A., Takizawa, F., Safdar, A., Manika, A., Tesmenitsky, Y., Kang, K. T., Bischoff, J., Kalwa, H., Sartoretto, J. L., Kamei, Y., Benjamin, L. E., Watada, H., Ogawa, Y., Higashikuni, Y., Kessinger, C. W., Jaffer, F. A., Michel, T., Sata, M., ... Arany, Z. (2014). Endothelial PGC-1α mediates vascular dysfunction in diabetes. Cell metabolism, 19(2), 246-258. https://doi.org/10.1016/j.cmet.2013.12.014