Threonine 532 phosphorylation in ClC-3 is required for angiotensin H-induced Cl- current and migrati

来源 :中国药理学会第十三次全国学术大会 | 被引量 : 0次 | 上传用户:yjn511
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  Aim Angiotensin Ⅱ (AngⅡ) induces vascular smooth muscle cell (VSMC) migration and growth, which is responsible for vascular remodeling during some cardiovascular diseases.It has been demonstrated to activate a Clcurrent, but the underlying mechanism is not clear.Methods Wholecell patch clamp, coimmunoprecipitation(coIP), sitespecific mutagenesis, angiotensinlinfusion hypertensive mice model were used.Results In VSMCs,AngⅡ could induce a ClC3dependent Clcurrent that was abolished in ClC3 null mice.The activation mechanism of this AngHinduced Clcurrent was ascribed to the interaction between ClC3 and Rhokinase 2 (ROCK2), as revealed by Nterminal or Cterminal truncation of ClC3, ROCK2 siRNA and CoIP experiments.Then we searched for and identified the phosphorylation site of ClC3 at threonine 532 is critical for AngⅡinduced Clcurrent and VSMC migration through ROCK.The ClC3 T532D mutant (mutation of threonine 532 to aspartate), mimicking the phosphorylation state of ClC3, significantly potentiated AngⅡinduced Clcurrent and VSMC migration; while ClC3T532A (mutation of threonine 532 to alanine) had the opposite effects.Furthermore, we found a remarkably decreased AngⅡinduced VSMC migration in ClC3 null mice that is insensitive to Y27632, an inhibitor of ROCK2.In addition, AngⅡinduced cerebrovascular remodeling was ameliorated in ClC3 null mice, possibly by ROCK2 pathway.Conclusions ClC3 protein phosphorylation at threonine 532 by ROCK2 is required for AngⅡinduced Clcurrent and VSMC migration that are involved in AngⅡinduced hypertensive vascular remodeling.
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