Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 173, Issue 3, Pages 529-544Publisher
WILEY
DOI: 10.1111/bph.13385
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Funding
- National Natural Science Foundation of China [81230082, 81173055, 81302771, 81370897, 81525025, 81473206, 81273500]
- CHINA-CANADA Joint Health Research Program from NSFC-CIHR [81361128011]
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Background and PurposeAngiotensin II (AngII) induces migration and growth of vascular smooth muscle cell (VSMC), which is responsible for vascular remodelling in some cardiovascular diseases. Ang II also activates a Cl- current, but the underlying mechanism is not clear. Experimental ApproachThe A10 cell line and primary cultures of VSMC from control, ClC-3 channel null mice and WT mice made hypertensive with AngII infusions were used. Techniques employed included whole-cell patch clamp, co-immunoprecipitation, site-specific mutagenesis and Western blotting, Key ResultsIn VSMC, AngII induced Cl- currents was carried by the chloride ion channel ClC-3. This current was absent in VSMC from ClC-3 channel null mice. The AngII-induced Cl- current involved interactions between ClC-3 channels and Rho-kinase 2 (ROCK2), shown by N- or C-terminal truncation of ClC-3 protein, ROCK2 siRNA and co-immunoprecipitation assays. Phosphorylation of ClC-3 channels at Thr(532) by ROCK2 was critical for AngII-induced Cl- current and VSMC migration. The ClC-3 T532D mutant (mutation of Thr(532) to aspartate), mimicking phosphorylated ClC-3 protein, significantly potentiated AngII-induced Cl- current and VSMC migration, while ClC-3 T532A (mutation of Thr(532) to alanine) had the opposite effects. AngII-induced cell migration was markedly decreased in VSMC from ClC-3 channel null mice that was insensitive to Y27632, an inhibitor of ROCK2. In addition, AngII-induced cerebrovascular remodelling was decreased in ClC-3 null mice, possibly by the ROCK2 pathway. Conclusions And ImplicationsClC-3 protein phosphorylation at Thr(532) by ROCK2 is required for AngII-induced Cl- current and VSMC migration that are involved in AngII-induced vascular remodelling in hypertension.
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