Effect of Olmesartan on Tissue Expression Balance Between Angiotensin II Receptor and Its Inhibitory Binding Molecule

Shigenaga, Atsu-ichiro; Tamura, Kouichi; Wakui, Hiromichi; Masuda, Shinichiro; Azuma, Koichi; Tsurumi‐Ikeya, Yuko; Ozawa, Motoko; Mogi, Masaki; Matsuda, Miyuki; Uchino, Kenji; Kimura, Kazuo; Horiuchi, Masatsugu; Umemura, Satoshi

doi:10.1161/hypertensionaha.108.117341

Cited by 24 publications

(26 citation statements)

References 33 publications

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“…We observed recently that treatment with an AT 1 R antagonist recovered a constitutive decrease in the ratio of cardiac expression of ATRAP/AT 1 R in spontaneously hypertensive rats, which was accompanied by a decrease in cardiac p38 activity and a suppression of cardiac hypertrophy. 30 Previous studies have shown that increases in cardiac p38 activity through the activation of AT 1 R signaling are profoundly involved in cardiac hypertrophy and the damage incurred in genetic and experimental hypertension models, including spontaneously hypertensive rats and Ang II infusion. 31,32 Because we had hypothesized that cardiac-specific upregulation of the ATRAP/AT 1 R ratio suppresses the cardiac hypertrophy induced by Ang II infusion, we produced the cardiomyocyte-specific ATRAP Tg mice, with a constitutively high expression of cardiac ATRAP and a resultant upregulation of the cardiac ATRAP/AT 1 R ratio, to examine this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Cardiac-Specific Activation of Angiotensin II Type 1 Receptor–Associated Protein Completely Suppresses Cardiac Hypertrophy in Chronic Angiotensin II–Infused Mice

Wakui

Tamura²,

Tanaka³

et al. 2010

Hypertension

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Abstract-We cloned a novel molecule interacting with angiotensin II type 1 receptor, which we named ATRAP (for angiotensin II type 1 receptor-associated protein). Previous in vitro studies showed that ATRAP significantly promotes constitutive internalization of the angiotensin II type 1 receptor and further attenuates angiotensin II-mediated hypertrophic responses in cardiomyocytes. The present study was designed to investigate the putative functional role of ATRAP in cardiac hypertrophy by angiotensin II infusion in vivo. We first examined the effect of angiotensin II infusion on endogenous ATRAP expression in the heart of C57BL/6J wild-type mice. The angiotensin II treatment promoted cardiac hypertrophy, concomitant with a significant decrease in cardiac ATRAP expression, but without significant change in cardiac angiotensin II type 1 receptor expression. We hypothesized that a downregulation of the cardiac ATRAP to angiotensin II type 1 receptor ratio is involved in the pathogenesis of cardiac hypertrophy. To examine this hypothesis, we next generated transgenic mice expressing ATRAP specifically in cardiomyocytes under control of the ␣-myosin heavy chain promoter. In cardiac-specific ATRAP transgenic mice, the development of cardiac hypertrophy, activation of p38 mitogen-activated protein kinase, and expression of hypertrophy-related genes in the context of angiotensin II treatment were completely suppressed, in spite of there being no significant difference in blood pressure on radiotelemetry between the transgenic mice and littermate control mice. These results demonstrate that cardiomyocyte-specific overexpression of ATRAP in vivo abolishes the cardiac hypertrophy provoked by chronic angiotensin II infusion, thereby suggesting ATRAP to be a novel therapeutic target in cardiac hypertrophy. (Hypertension. 2010;55:1157-1164.)Key Words: basic science Ⅲ receptors Ⅲ gene expression/regulation Ⅲ hypertrophy/remodeling Ⅲ angiotensin receptors E vidence suggests that the activation of angiotensin II (Ang II) type 1 receptor (AT 1 R) through the tissue renin-angiotensin system may play an important role in the development of cardiac hypertrophy. The carboxyl-terminal portion of AT 1 R is involved in the control of AT 1 R internalization independent of G protein coupling, and it plays an important role in linking receptor-mediated signal transduction to the specific biological response to Ang II. 1,2 We previously cloned a novel AT 1 R-associated protein (ATRAP) that specifically interacts with the carboxylterminal domain of AT 1 R. [3][4][5][6] We showed that ATRAP is broadly expressed in many tissues, as is AT 1 R, and suppresses Ang II-mediated pathological responses in cardiomyocytes and vascular smooth muscle cells by promoting the constitutive internalization of AT 1 R. 7-9 However, the function of ATRAP in cardiac hypertrophy in vivo still remains to be demonstrated. Thus, the present study was carried out to investigate whether there is a role for ATRAP in the cardiac hypertrophy induced by chronic Ang II ...

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Section: Discussionmentioning

confidence: 99%

Cardiac-Specific Activation of Angiotensin II Type 1 Receptor–Associated Protein Completely Suppresses Cardiac Hypertrophy in Chronic Angiotensin II–Infused Mice

Wakui

Tamura²,

Tanaka³

et al. 2010

Hypertension

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“…We showed that there is a tissuespecific regulatory balancing of the expression of ATRAP and AT1R during the development of hypertension in spontaneously hypertensive rats (SHRs) [19]. The activation of ATRAP in transgenic-models in which ATRAP expression was increased beyond baseline promoted Ang II-mediated AT1R internalization and inhibited renal angiotensinogen production and cardiac hypertrophy in response to Ang II stimulation [20].…”

Section: Introductionmentioning

confidence: 99%

Prepubertal angiotensin blockade exerts long-term therapeutic effect through sustained ATRAP activation in salt-sensitive hypertensive rats

Dejima

Tamura²,

Wakui³

et al. 2011

Journal of Hypertension

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“…Juvenile RAS blockade during a "critical period" results in prolonged blood pressure-lowering and organ protection that remains for a prolonged time after drug withdrawal (Shigenaga et al, 2008). Reduced angiotensin sensitivity has been attributed as a potential mechanism for this phenomenon.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, ATRAP was up-regulated in prehypertensively treated SHHF. Because ATRAP has been demonstrated to be an endogenous inhibitor of AT1R signaling in cardiovascular cells (Shigenaga et al, 2008), the upregulation of ATRAP in cardiovascular tissue may add to the therapeutic benefits of the preconditioning.…”

Section: Discussionmentioning

confidence: 99%

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Prehypertensive Preconditioning Improves Adult Antihypertensive and Cardioprotective Treatment

Baumann¹,

Sollinger²,

Roos³

et al. 2009

J Pharmacol Exp Ther

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Transient prehypertensive treatment (TPT) causes prolonged antihypertensive and cardioprotective effects. Reduced angiotensin sensitivity has been attributed to those effects. We hypothesize that prehypertensive preconditioning by angiotensin II type 1 receptor (AT1R) blockade improves cardiovascular protection of late-onset AT1R blockade in a model of spontaneous hypertensive heart-failure rats (SHHF/Mcc-fa cp ). TPT (4 -8 weeks of age) consisted of AT1R blockade (5 mg/kg candesartan) or vehicle. Candesartan-pretreated SHHF (5 mg/ kg/day candesartan; weeks 4 -8) received during adulthood (20 -28 weeks of age) either candesartan at a dose of 1.5 or 5 mg/kg/day or vehicle. Vehicle-pretreated SHHF received either candesartan (5 mg/kg/day) or vehicle during adulthood. Blood pressure telemetry and longitudinal echocardiography were performed between weeks 20 and 28. Final examination included cardiac and vascular morphometry and measurement of the AT1R signaling and receptor internalization (ATRAP). Combined juvenile and adult AT1R blockade caused lower mean arterial pressure (MAP) than adult AT1R blockade alone (84 Ϯ 5 versus 97 Ϯ 5 mm Hg; P Ͻ 0.05). Cardiac and vascular hypertrophy was lower. Juvenile treatments were associated with a reduced cardiovascular AT1R expression and enhanced ATRAP expression. Combined juvenile and reduced adult AT1R blockade resulted in MAP similar to that with adult AT1R blockade alone (92 Ϯ 3 versus 97 Ϯ 5 mm Hg). We conclude that prehypertensive preconditioning improves adult treatment effects in SHHF. Those effects correlate with reduced cardiovascular AT1R expression and enhanced receptor internalization, suggesting reduced angiotensin sensitivity in pretreated SHHF. Moreover, preconditioning allows a reduction of adult AT1R blockade without loss of protection. Therefore, prehypertensive preconditioning may offer a tool to improve treatment efficacy in humans.The awareness of hypertension is poor and, consequently, so is appropriate antihypertensive treatment (Cutler et al., 2008). Therefore, alternative treatment strategies for hypertension and cardiovascular complications are of particular interest. The trial of preventing hypertension (TROPHY) was the first clinical study to demonstrate that a transient prehypertensive treatment (TPT) could successfully delay new onset of hypertension in a cohort of prehypertensive subjects 2 years after withdrawal of an angiotensin II type 1 receptor (AT1R) blocker compared with placebo (Julius et al., 2006). However, TROPHY raised the concern that TPT was a promotion for earlier use of antihypertensive drugs rather than a reliable and efficient addition to antihypertensive treatment (AHT) (Baumann and van den Born, 2006;Grassi, 2006;Meltzer, 2006;Persell and Baker, 2006;Nesbitt, 2007). Indeed, this context has not been investigated in detail. Thus, it remains unclear whether TPT is as effective in blood pressure-lowering and end-organ protection as continuous AHT starting at adulthood. Up to now, the potential preconditioning effects o...

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Effect of Olmesartan on Tissue Expression Balance Between Angiotensin II Receptor and Its Inhibitory Binding Molecule

Cited by 24 publications

References 33 publications

Cardiac-Specific Activation of Angiotensin II Type 1 Receptor–Associated Protein Completely Suppresses Cardiac Hypertrophy in Chronic Angiotensin II–Infused Mice

Cardiac-Specific Activation of Angiotensin II Type 1 Receptor–Associated Protein Completely Suppresses Cardiac Hypertrophy in Chronic Angiotensin II–Infused Mice

Prepubertal angiotensin blockade exerts long-term therapeutic effect through sustained ATRAP activation in salt-sensitive hypertensive rats

Prehypertensive Preconditioning Improves Adult Antihypertensive and Cardioprotective Treatment

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