doi: 10.1161/CIRCRESAHA.108.177295
© 2008 American Heart Association, Inc.
Editorials |
Triple Twist Theory of Rho Inhibition by the Angiotensin II Type 2 Receptor
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{at}temple.edu
Key Words: angiotensin II • Rho • AT2 receptor • signal transduction • vasodilation
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 (Gi or Gs) 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 for RhoA inhibition by the AT2 receptor (see Figure 7 in the article). Although negative regulation of RhoA through its Ser188 phosphorylation by the AT2 receptor has been demonstrated,12,13 the 2 kinases (casein kinase II [CK2] and Ste20-related kinase SLK) are novel downstream elements of the AT2 receptor.
By using multiple distinct molecular approaches, a novel signal transduction cascade for inhibition of RhoA via the AT2 receptor, which is expected to counterregulate RhoA activation by the AT1 receptor in VSMCs, becomes apparent (Figure).11 Rho kinase (ROCK), the best-characterized effector of the small G protein RhoA, contributes to vascular contraction via Ca2+ sensitization. Moreover, the Rho/ROCK pathway has been implicated in a wide variety of cardiovascular pathogenic conditions, including hypertension, atherosclerosis, and cardiovascular hypertrophy.14–17 It should be noted that both heterotrimeric G protein-dependent and -independent signal transductions have been proposed to mediate AT1 receptor function.4,18,19 In addition to the production of reactive oxygen species4 and enhanced VSMC contraction, hypertrophy, as well as migration induced by the AT1 receptor, seems to require at least two parallel signal transduction cascades mediated through Gq and G12/13. The latter is primarily implicated in the Rho/ROCK cascade activation via RGS (regulator of G protein signaling)-domain containing Rho guanine nucleotide exchange factors (RhoGEFs).20–23 Inhibition of either cascade appears to block those pathogenic functions induced by the AT1 receptor,20–23 and the study by Guilluy et al11 has further demonstrated that the RhoA inhibition mechanism via the AT2 receptor in VSMCs results in vasodilation.11 The findings also indicate a strong support of this potential "triple twist" RhoA inhibition theory to explain the multiple tissue protective effects of AT1 receptor blockers beyond the expected AT1 inhibition, because the AT2 receptors could be strongly stimulated under these treatments.
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In addition, identification of the novel key components of the AT2 signal transduction will aid in exploring the molecular insight regarding the dynamic regulation of cardiovascular remodeling via the AT1 versus AT2, which likely involves far more additional crosstalk. Both cAMP- and cGMP-dependent kinases have been shown to phosphorylate RhoA at Ser188,24 which, in part, explains the vasodilatory properties of these kinases in VSMCs. The study by Guilluy et al has identified SLK as a novel RhoA Ser188 kinase.11 Interestingly, SLK has been shown to be able to activate apoptosis signal-regulated kinase-1 (ASK1) and p38 MAPK, leading to cell apoptosis.25 This fits well with the past findings that AT2 mediates apoptosis in VSMCs via p38 MAPK activation.26 Regarding CK2, activation of CK2 has been recently shown to mediate p27 degradation by angiotensin II likely through the AT1 receptor, which leads to cardiac hypertrophy.27 The p27 degradation has also been implicated in vascular hyperplasia.28 Therefore, inhibition of CK2 activity by the AT2 receptor may also antagonize the AT1 mediated detrimental effects through stabilization of p27 in addition to the RhoA inhibition.
Because the findings by Guilluy et al11 were mostly limited to VSMC culture and a ex vivo deendothelialized contraction assay using rat thoracic aorta rings, the relevance of this novel AT2 signal transduction in mediating the beneficial AT2 function in cardiovascular diseases remains unclear. Further expansion of the research in this field by using animal models of cardiovascular diseases has strong potential for future translation of the outcomes, which may lead to prevention of cardiovascular diseases linked to enhanced AT1 receptor signal transduction.
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Acknowledgments |
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I thank Dr Gerald D. Frank for critical reading of this comment.
Sources of Funding
Some of the work by the author referenced in this editorial was funded by NIH grant HL076770, American Heart Association Established Investigator Award 0740042N, and the W.W. Smith Charitable Trust grant H0605.
Disclosures
None.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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