Deletion of the protein kinase A/protein kinase G target SMTNL1 promotes an exercise-adapted phenotype in vascular smooth muscle |
| |
Authors: | Wooldridge Anne A Fortner Christopher N Lontay Beata Akimoto Takayuki Neppl Ronald L Facemire Carie Datto Michael B Kwon Ashley McCook Everett Li Ping Wang Shiliang Thresher Randy J Miller Sara E Perriard Jean-Claude Gavin Timothy P Hickner Robert C Coffman Thomas M Somlyo Avril V Yan Zhen Haystead Timothy A J |
| |
Institution: | Department of Pharmacology, Medicine, Duke University, Medical Center, Durham, North Carolina 27710, USA. |
| |
Abstract: | In vivo protein kinases A and G (PKA and PKG) coordinately phosphorylate a broad range of substrates to mediate their various physiological effects. The functions of many of these substrates have yet to be defined genetically. Herein we show a role for smoothelin-like protein 1 (SMTNL1), a novel in vivo target of PKG/PKA, in mediating vascular adaptations to exercise. Aortas from smtnl1(-/-) mice exhibited strikingly enhanced vasorelaxation before exercise, similar in extent to that achieved after endurance training of wild-type littermates. Additionally, contractile responses to alpha-adrenergic agonists were greatly attenuated. Immunological studies showed SMTNL1 is expressed in smooth muscle and type 2a striated muscle fibers. Consistent with a role in adaptations to exercise, smtnl1(-/-) mice also exhibited increased type 2a fibers before training and better performance after forced endurance training compared smtnl1(+/+) mice. Furthermore, exercise was found to reduce expression of SMTNL1, particularly in female mice. In both muscle types, SMTNL1 is phosphorylated at Ser-301 in response to adrenergic signals. In vitro SMTNL1 suppresses myosin phosphatase activity through a substrate-directed effect, which is relieved by Ser-301 phosphorylation. Our findings suggest roles for SMTNL1 in cGMP/cAMP-mediated adaptations to exercise through mechanisms involving direct modulation of contractile activity. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|