Abstract-The small G protein Rho signaling pathways are recognized as major regulators of cardiovascular functions, and activation of Rho proteins appears to be a common component for the pathogenesis of hypertension and vascular proliferative disorders. Recent evidence suggests that modulation of Rho protein signaling by phosphorylation of Rho proteins provides an additional simple mechanism for coordinating Rho protein functions. Phosphorylation of RhoA by cAMP-or cGMP-activated kinase on Ser188 induces cytosolic sequestration of RhoA through increased interaction with guanine dissociation inhibitor, thereby resulting in inhibition of RhoA-dependent functions. Here we show that stimulation of angiotensin II (Ang II) type 2 receptor (AT 2 R) in vascular smooth muscle cells induces Ser188 phosphorylation of RhoA independently of cAMP-or cGMP-activated kinase. We identify the Ser/Thr kinase Ste20-related kinase SLK as a new kinase phosphorylating RhoA on Ser188. Activation of the signaling cascade involving Src homology 2 domain-containing protein-tyrosine phosphatase 1, casein kinase II and SLK is responsible for RhoA phosphorylation and inhibition of RhoA-mediated arterial contraction induced by AT 2 R activation. These results thus identify the molecular mechanism linking AT 2 R to RhoA inhibition and vasodilation. (Circ Res. 2008;102:1265-1274.)Key Words: Rho Ⅲ signal transduction Ⅲ phosphorylation Ⅲ angiotensin II Ⅲ vascular smooth muscle R hoA is a member of the Rho protein family that has been identified as an essential regulator of vascular smooth muscle cell functions. Through the activation of its target Rho kinase, RhoA is the major regulator of the tonic component of vascular smooth muscle cell contraction and plays a critical role in the control of vascular smooth muscle differentiation, proliferation, and migration. 1 Subsequent studies have demonstrated the participation of the RhoA/Rho kinase signaling pathway in several vascular pathologies, including hypertension, coronary artery spasm, effort angina, atherosclerosis, and restenosis. 1,2 Indeed, although basal RhoA activity is required for homeostatic functions in physiological conditions, its sustained overactivation has pathological consequences in the vascular system, particularly in vascular smooth muscle cells. Activation of RhoA-dependent pathways is involved in excessive contraction, and thereby increases blood pressure but also in excessive cell growth and migration that participate in pathological cardiovascular remodeling. 1 RhoA acts as a molecular switch. In the inactive GDPbound form, RhoA is locked in the cytosol by guanine dissociation inhibitors (GDIs). In the active GTP-bound form released from GDI, RhoA translocates to plasma membrane where it interacts with effectors to transduce the signal downstream. GTPase-activating proteins then turn off activation. In addition to this regulation, we and others have demonstrated that phosphorylation/dephosphorylation cycle also controls RhoA activity. 3 Cyclic GMP-dependent protein kinase...

Mutations of SCN5A gene, which encodes the α-subunit of the voltage-gated Na channel Na V 1.5, underlie hereditary cardiac arrhythmic syndromes such as the type 3 long QT syndrome, cardiac conduction diseases, the Brugada syndrome, the sick sinus syndrome, a trial standstill, and numerous overlap syndromes. Patch-clamp studies in heterologous expression systems have provided important information to understand the genotype-phenotype relationships of these diseases. However, they could not clarify how SCN5A mutations can be responsible for such a large spectrum of diseases, for the late age of onset or the progressiveness of some of these diseases and for the overlapping syndromes. Genetically modified mice rapidly appeared as promising tools for understanding the pathophysiological mechanisms of cardiac SCN5A-related arrhythmic syndromes and several mouse models have been established. This review presents the results obtained on these models that, for most of them, recapitulate the clinical phenotypes of the patients. This includes two models knocked out for Nav1.5 β1 and β3 auxiliary subunits that are also discussed. Despite their own limitations that we point out, the mouse models still appear as powerful tools to elucidate the pathophysiological mechanisms of SCN5A-related diseases and offer the opportunity to investigate the secondary cellular consequences of SCN5A mutations such as the expression remodeling of other genes. This points out the potential role of these genes in the overall human phenotype. Finally, they constitute useful tools for addressing the role of genetic and environmental modifiers on cardiac electrical activity.