OBJECTIVE: The regulation of AMP-activated protein kinase (AMPK) is implicated in vascular biology because AMPK can phosphorylate endothelial NO synthase (eNOS). In this study, we investigate the regulation of the AMPK-eNOS pathway in vascular endothelial cells (ECs) by shear stress and the activation of aortic AMPK in a mouse model with a high level of voluntary running (High-Runner). METHODS AND RESULTS: By using flow channels with cultured ECs, AMPK Thr172 phosphorylation was increased with changes of flow rate or pulsatility. The activity of LKB1, the upstream kinase of AMPK, and the phosphorylation of eNOS at Ser1179 were concomitant with AMPK activation responding to changes in flow rate or pulsatility. The blockage of AMPK by a dominant-negative mutant of AMPK inhibited shear stress-induced eNOS Ser1179 phosphorylation and NO production. Furthermore, aortic AMPK activity and level of eNOS phosphorylation were significantly elevated in the aortas of High-Runner mice. CONCLUSIONS: Our results suggest that shear stress activates AMPK in ECs, which contributes to elevated eNOS activity and subsequent NO production. Hence, AMPK, in addition to serving as an energy sensor, also plays an important role in regulating vascular tone.
OBJECTIVE: The regulation of AMP-activated protein kinase (AMPK) is implicated in vascular biology because AMPK can phosphorylate endothelial NO synthase (eNOS). In this study, we investigate the regulation of the AMPK-eNOS pathway in vascular endothelial cells (ECs) by shear stress and the activation of aortic AMPK in a mouse model with a high level of voluntary running (High-Runner). METHODS AND RESULTS: By using flow channels with cultured ECs, AMPK Thr172 phosphorylation was increased with changes of flow rate or pulsatility. The activity of LKB1, the upstream kinase of AMPK, and the phosphorylation of eNOS at Ser1179 were concomitant with AMPK activation responding to changes in flow rate or pulsatility. The blockage of AMPK by a dominant-negative mutant of AMPK inhibited shear stress-induced eNOS Ser1179 phosphorylation and NO production. Furthermore, aortic AMPK activity and level of eNOS phosphorylation were significantly elevated in the aortas of High-Runner mice. CONCLUSIONS: Our results suggest that shear stress activates AMPK in ECs, which contributes to elevated eNOS activity and subsequent NO production. Hence, AMPK, in addition to serving as an energy sensor, also plays an important role in regulating vascular tone.
Authors: Swenja Kröller-Schön; Thomas Jansen; Felix Hauptmann; Andrea Schüler; Tjebo Heeren; Michael Hausding; Matthias Oelze; Benoit Viollet; John F Keaney; Philip Wenzel; Andreas Daiber; Thomas Münzel; Eberhard Schulz Journal: Arterioscler Thromb Vasc Biol Date: 2012-04-26 Impact factor: 8.311
Authors: Kristen A Baltgalvis; Kathy White; Wei Li; Mark D Claypool; Wayne Lang; Raniel Alcantara; Baljit K Singh; Annabelle M Friera; John McLaughlin; Derek Hansen; Kelly McCaughey; Henry Nguyen; Ira J Smith; Guillermo Godinez; Simon J Shaw; Dane Goff; Rajinder Singh; Vadim Markovtsov; Tian-Qiang Sun; Yonchu Jenkins; Gerald Uy; Yingwu Li; Alison Pan; Tarikere Gururaja; David Lau; Gary Park; Yasumichi Hitoshi; Donald G Payan; Todd M Kinsella Journal: Am J Physiol Heart Circ Physiol Date: 2014-02-21 Impact factor: 4.733
Authors: Brendan Gongol; Traci Marin; I-Chen Peng; Brian Woo; Marcy Martin; Stephanie King; Wei Sun; David A Johnson; Shu Chien; John Y-J Shyy Journal: Proc Natl Acad Sci U S A Date: 2013-02-04 Impact factor: 11.205