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(Circulation Research. 2008;102:1143.)
© 2008 American Heart Association, Inc.

Editorials

Triple Twist Theory of Rho Inhibition by the Angiotensin II Type 2 Receptor

Satoru Eguchi

From the Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, Pa.

Correspondence to Satoru Eguchi, MD, PhD, FAHA, Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, 3420 N Broad St, Philadelphia, PA 19140. E-mail seguchi@temple.edu

Key Words: angiotensin II • Rho • AT₂ receptor • signal transduction • vasodilation

An extract of the first 250 words of the full text is provided, because this article has no abstract.

Although there are some exceptions,^1,2 numerous publications support the counterregulatory roles of the angiotensin II type 2 receptor (AT₂) against the AT₁ receptor functions, such as inhibition of vascular contraction and hypertrophy.^3–5 However, it is still very uncertain as to how the AT₂ receptor signals interfere with those of the AT₁ receptor in the cardiovascular system.^5,6 Past findings suggest that the signal transduction of AT₁ inhibition by the AT₂ receptor may involve multiple distinct mechanisms. Some of these mechanisms appear to be indirect, such as production of nitric oxide through bradykinin opposing the vasoconstrictor actions of the AT₁ receptor.³ The direct inhibitory crosstalk of the 2 receptors occurs proximal to the receptor heterodimerization, as well as downstream from the receptors between AT₁-activated protein kinases epidermal growth factor receptor kinase and extracellular signal-regulated kinase (ERK)1/2/p42/44 mitogen-activated protein kinase (MAPK), etc and AT₂-activated protein phosphatases protein phosphatase 2A, SHP-1, and MAPK phosphatase-1.^7,8 The activation of the protein phosphatases by the AT₂ receptor may or may not require heterotrimeric G proteins (G_i or G_s) and/or the recently identified AT₂ receptor C-terminal tail–interacting proteins.^4–6

Given that induction of hypertrophy of vascular smooth muscle cells (VSMCs) via the AT₁ receptor appears to require a "triple-membrane-passing signal" involving a metalloprotease-dependent epidermal growth factor receptor transactivation,^9,10 the article by Guilluy et al in this issue of Circulation Research¹¹ may not be so surprising, because it suggests the requirement of rather "twisty" 3 sequential phosphorylation/dephosphorylation events between a phosphatase, SHP-1, and 2 protein kinases . . . [Full Text of this Article]

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				K. Kimura and S. Eguchi Angiotensin II type-1 receptor regulates RhoA and Rho-kinase/ROCK activation via multiple mechanisms. Focus on "Angiotensin II induces RhoA activation through SHP2-dependent dephosphorylation of the RhoGAP p190A in vascular smooth muscle cells" Am J Physiol Cell Physiol, November 1, 2009; 297(5): C1059 - C1061. [Full Text] [PDF]