CapZ dynamics are altered by endothelin-1 and phenylephrine via PIP2- and PKC-dependent mechanisms

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American Physiological Society

RESUMO

One of the unanswered questions in muscle hypertrophy is how new contractile units are inserted into a stable existing cytoskeletal meshwork. Regulation of actin capping by CapZ may play a role in remodeling processes, therefore, CapZ dynamics are determined during rapid growth of cardiac cells in vitro. Neonatal rat ventricular myocytes were infected with adenovirus expressing green fluorescent protein-CapZ β1 and responded normally to hypertrophic stimuli. CapZ dynamics were analyzed by fluorescence recovery after photobleaching in cultured myocytes treated with endothelin-1 (100 nM) or phenylephrine (10 μM). Recovery by 30 s was greater with endothelin treatment. Analysis 30 min postbleach showed CapZ-infected cells treated with endothelin recovered more completely than controls (77 ± 9% vs. 50 ± 6%, P < 0.001). Similar results were found with phenylephrine (77 ± 5%, P < 0.05). A potential mechanism for phosphatidylinositol bisphosphate (PIP2) mediation of increased CapZ exchange in endothelin- and phenylephrine-treated cells was tested. PIP2 sequestration with neomycin (500 μM) blocked both endothelin- (43 ± 6%, P < 0.001) and phenylephrine (36 ± 4%, P < 0.001)-mediated recovery. The protein kinase C inhibitor chelerythrine chloride (10 μM) also blocked endothelin- (53 ± 10%, P < 0.001) and phenylephrine (42 ± 3%, P < 0.001)-mediated recovery. This study demonstrates for the first time that endothelin and phenylephrine alter CapZ dynamics through PIP2- and PKC-dependent pathways, which might destabilize the existing framework and permit sarcomeric remodelling to proceed.

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