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PKCα-Mediated Downregulation of RhoA Activity in Depolarized Vascular Smooth Muscle: Synergistic Vasorelaxant Effect of PKCα and ROCK Inhibition

AuthorsGonzález-Montelongo, María del Carmen; Porras-González, Cristina; González-Montelongo, Rafaela; Revilla-González, Gonzalo; Pastor, María Dolores; Castellano, Antonio; Ureña, Juan
KeywordsProtein kinase C (PKC)
Rho (Rho GTPase)
Vascular smooth muscle cells
Calcium channel
Cell signaling
Phorbol ester
Issue Date2019
PublisherS. Karger AG
CitationCellular Physiology and Biochemistry 52: 76-93 (2019)
Abstract[Background/Aims] Protein kinase C (PKC)- and RhoA/Rho-associated kinase (ROCK) play important roles in arterial sustained contraction. Although depolarization-elicited RhoA/ROCK activation is accepted, the role of PKC in depolarized vascular smooth muscle cells (VSMCs) is a subject of controversy. Our aim was to study the role of PKC in arterial contraction and its interaction with RhoA/ROCK.
[Methods] Mass spectrometry was used to identify the PKC isoenzymes. PKCα levels and RhoA activity were analyzed by western blot and G-LISA, respectively, and isometric force was measured in arterial rings.
[Results] In depolarized VSMCs RhoA and PKCα were translocated to the plasma membrane, where they colocalize and coimmunoprecipitate. Interestingly, depolarization-induced RhoA activation was downregulated by PKCα, effect reverted by PKCα inhibition. Phorbol 12,13-dibutyrate (PDBu) induced the translocation of PKCα to the plasma membrane, increased the level of RhoA in the cytosol and reduced RhoA/ROCK activity. These effects were reverted when PKC was inhibited. Pharmacological or siRNA inhibition of PKCα synergistically potentiated the vasorelaxant effect of RhoA/ROCK inhibition.
[Conclusion] The present study provides the first evidence that RhoA activity is downregulated by PKCα in depolarized and PDBu treated freshly isolated VSMCs and arteries, with an important physiological role on arterial contractility.
Publisher version (URL)http://dx.doi.org/10.33594/000000006
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