title: Smooth muscle 22α facilitates angiotensin II-induced signaling and vascular contraction.
abstract: Smooth muscle 22α (SM22α) is involved in stress fiber formation and enhances contractility in vascular smooth muscle cells (VSMCs). In many cases, SM22α acts as an adapter protein to assemble signaling complexes and regulate signaling, but whether SM22α regulates contractile signaling induced by angiotensin II (AngII) remains unclear. To address this issue, we established a hypertension model of Sm22α(-/-) mice, and demonstrated that hypertension induced by AngII was attenuated in Sm22α(-/-) mice. A decreased vasoconstriction was observed in aortic rings from Sm22α(-/-) mice. Furthermore, loss of SM22α resulted in a reduced contractile response to AngII in VSMCs in vitro. The phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) induced by AngII was impaired following depletion of SM22α, in parallel with a reduced contractility. The decay of ERK1/2 activity was associated with increased expression of mitogen-activated protein kinase phosphatase 3 (MKP3). Inhibition of MKP3 activity rescued ERK1/2 activity. SM22α depletion caused an enhanced interaction of MKP3 with ERK1/2, and a reduced ubiquitination and degradation of MKP3. Knockdown of SM22α extended the half-life of MKP3. In conclusion, SM22α promotes AngII-induced contraction by maintenance of ERK1/2 signaling cascades through facilitating ubiquitination and degradation of MKP3.
  
  
  CONCLUSIONS
  The vasoconstriction is attenuated in aortic rings from Sm22α(-/-) mice. MKP3 mediates dephosphorylation of ERK1/2 in AngII-induced VSMC contraction. SM22α inhibits the interaction of ERK1/2 with MKP3. SM22α promotes ubiquitination and degradation of MKP3. SM22α facilitates AngII-induced contraction by maintenance of ERK1/2 signaling.
authors.affiliation: Key Laboratory of Medical Biotechnology of Hebei Province, Key Laboratory of Neural and Vascular Biology of Ministry of Education, Department of Biochemistry and Molecular Biology, College of Basic Medicine, Hebei Medical University, No. 361 Zhongshan East Road, Shijiazhuang, 050017, People's Republic of China.
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Xie
authors.forename: Xi
authors.initials: X
authors.lastname: Nie
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Zhao
authors.forename: Yan-Ling
authors.initials: YL
authors.lastname: Lin
authors.forename: Ya-Juan
authors.initials: YJ
authors.lastname: Yin
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.forename: Ya-Nan
authors.initials: YN
authors.lastname: Shu
authors.forename: Sui-Bing
authors.initials: SB
authors.lastname: Miao
authors.forename: Huan
authors.initials: H
authors.lastname: Li
authors.forename: Peng
authors.initials: P
authors.lastname: Chen
authors.forename: Mei
authors.initials: M
authors.lastname: Han
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D054642:Dual Specificity Phosphatase 6 / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects* / Q000235:genetics*; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D059748:Proteolysis; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D008840:Microfilament Proteins; D009124:Muscle Proteins; C051615:transgelin; D000804:Angiotensin II; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054642:Dual Specificity Phosphatase 6; C517036:Dusp6 protein, mouse; D046988:Proteasome Endopeptidase Complex