Conformational switch of angiotensin II type 1 receptor underlying mechanical stress‐induced activation

Yasuda, Noritaka; Miura, Shin‐ichiro; Akazawa, Hiroshi; Tanaka, Toshimasa; Qin, Yingjie; Kiya, Yoshihiro; Imaizumi, Satoshi; Fujino, Masahiro; Ito, Kei; Zou, Yunzeng; Fukuhara, Shigetomo; Kunimoto, Satoshi; Fukuzaki, Koichi; Sato, Toshiaki; Ge, Junbo; Mochizuki, Naoki; Nakaya, Haruaki; Saku, Keijiro; Komuro, Issei

doi:10.1038/sj.embor.7401157

Cited by 167 publications

(170 citation statements)

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“…Furthermore, previous studies have demonstrated differences between TLM and CAN. [36][37][38][39] Both TLM and CAN show clear efficacies. 36 However, the efficacy of CAN is linked to the presence of a carboxyl group at its imidazole-derived moiety, whereas TLM is efficacious despite the absence of a carboxyl group.…”

Section: Discussionmentioning

confidence: 99%

“…36 Moreover, in terms of inverse agonist activity, previous studies have demonstrated that CAN can stabilize AT 1 R in an inactive state, therefore acting as an 'inverse agonist,' in the absence of angiotensin II, whereas TLM does not have Sympathoinhibition by telmisartan in hypertensive rats T Kishi et al such an effect. [37][38][39] In terms of the agonist activity of peroxisome proliferator-activated receptor (PPAR)-g, a previous study suggested that orally administered rosiglitazone, a PPAR-g agonist, promotes a central antihypertensive effect via upregulation of PPAR-g and alleviation of oxidative stress in the RVLM of SHR. 40 Although both TLM and CAN function as partial agonists of PPAR-g, only TLM achieves this effect at therapeutic doses.…”

Section: Discussionmentioning

confidence: 99%

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Sympathoinhibition caused by orally administered telmisartan through inhibition of the AT1 receptor in the rostral ventrolateral medulla of hypertensive rats

2012

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In patients and animals with hypertension, sympathetic nervous system (SNS) activation is present. We have demonstrated that angiotensin II type 1 receptor (AT 1 R)-induced oxidative stress in the rostral ventrolateral medulla (RVLM), a vasomotor center in the brainstem, causes SNS activation in hypertensive rats. The aim of the present study was to determine whether orally administered AT 1 R blockers (ARBs) inhibit SNS activation through an anti-oxidant effect via inhibition of AT 1 R in the RVLM of hypertensive rats and, if so, whether the benefits are class effects of ARBs. Stroke-prone spontaneously hypertensive rats (SHRSPs), a hypertensive model with sympathoexcitation, were divided into four groups: SHRSPs treated with telmisartan (TLM), candesartan (CAN), or hydralazine (HYD) and a vehicle group (VEH). Although systolic blood pressure was reduced in the TLM, CAN and HYD groups to the same level, heart rate, SNS activation and oxidative stress in the RVLM were significantly lower in the TLM group only. The pressor effect caused by the microinjection of angiotensin II into the RVLM and the depressor effect caused by the microinjection of tempol, a superoxide dismutase mimetic, into the RVLM were both significantly smaller in TLM, but not in CAN or HYD. These results suggest that orally administered TLM inhibits SNS activation through an anti-oxidant effect via inhibition of AT 1 R in the RVLM of SHRSPs; these results are also independent of depressor effects and are not class effects of ARBs. Keywords: angiotensin II; brain; oxidative stress; sympathetic nervous system INTRODUCTION Sympathetic nervous system (SNS) activation is a main cause of the development and progression of hypertension. 1-4 SNS activation is mainly regulated by the brain, 5-7 and we have demonstrated in rat models with hypertension or heart failure that direct interventions to the brain have beneficial effects because of sympathoinhibition. [8][9][10][11][12][13][14] Particularly in the brain, SNS activation is mainly regulated by the rostral ventrolateral medulla (RVLM) in the brainstem, and the functional integrity of the RVLM is essential for the maintenance of basal vasomotor tone. 5,6 We have demonstrated that oxidative stress in the RVLM produced by the angiotensin II type 1 receptor (AT 1 R) causes SNS activation. 11,14-17 Upregulation of the central AT 1 R is important in the pathophysiology of hypertension. 6,7 Microinjection of AT 1 R blockers (ARBs) into the RVLM or intracerebroventricular infusion of ARBs inhibits SNS activation in hypertensive rats. 15,[18][19][20] However, AT 1 R or oxidative stress in the RVLM have not been targets for the treatment of hypertensive patients because we do not have suitable oral agents to inhibit AT 1 R or oxidative stress in the RVLM of hypertensive patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Sympathoinhibition caused by orally administered telmisartan through inhibition of the AT1 receptor in the rostral ventrolateral medulla of hypertensive rats

2012

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“…The expression vector for AT 1 -WT and AT 1 -mutant receptors 9 was transfected using FuGENE 6 Transfection Reagent (Roche Diagnostics, Basel, Switzerland) according to the manufacturer's instructions. 7 …”

Section: Cell Culture and Transfectionmentioning

confidence: 99%

“…9 However, studies using substituted cysteine accessibility mapping (SCAM) showed that conformation of the AT 1 p-ERKs during stretch-induced activation is quite different from that of the AT 1 -N111G receptor. 7,10 Transmembrane domain 7 (TM7) of the AT 1 receptor undergoes a counterclockwise rotation and a shift toward the ligand-binding pocket in response to mechanical stretch, 7 but it shifts away from the ligand-binding pocket in the AT 1 -N111G receptor. 10 In this study, we show that, as an inverse agonist, olmesartan strongly inhibits the stretch-induced activation of the AT 1 receptor, as well as the constitutive activity of the AT 1 -N111G receptor.…”

Section: Introductionmentioning

confidence: 99%

“…5 The AT 1 receptor is also activated by the mechanical stress of cellular stretching without the involvement of AngII. 6,7 A ligand capable of suppressing the agonist-independent activities of a receptor is defined as an inverse agonist. 5,8 We have previously reported that pressure overload induces cardiac hypertrophy in angiotensinogen-deficient mice as well as in wild-type (WT) mice and that hypertrophy is significantly attenuated by the inverse agonist, candesartan.…”

Section: Introductionmentioning

confidence: 99%

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Multivalent ligand–receptor interactions elicit inverse agonist activity of AT1 receptor blockers against stretch-induced AT1 receptor activation

et al. 2009

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Type 1 angiotensin II (AT 1 ) receptor has a critical role in the development of load-induced cardiac hypertrophy. Recently, we showed that mechanical stretching of cells activates the AT 1 receptor without the involvement of angiotensin II (AngII) and that this AngII-independent activation is inhibited by the inverse agonistic activity of the AT 1 receptor blocker (ARB), candesartan. Although the inverse agonist activity of ARBs has been studied in terms of their action on constitutively active AT 1 receptors, the structure-function relationship of the inverse agonism they exert against stretch-induced AT 1 receptor activation has not been fully elucidated. Assays evaluating c-fos gene expression and phosphorylated extracellular signal-regulated protein kinases (ERKs) have shown that olmesartan has strong inverse agonist activities against the constitutively active AT 1 receptor and the stretch-induced activation of AT 1 receptor, respectively. Ternary drug-receptor interactions, which occur between the hydroxyl group of olmesartan and Tyr 113 and between the carboxyl group of olmesartan and Lys 199 and His 256 , were essential for the potent inverse agonist action olmesartan exerts against stretch-induced ERK activation and the constitutive activity of the AT 1 -N111G mutant receptor. Furthermore, the inverse agonist activity olmesartan exerts against stretch-induced ERK activation requires an additional drug-receptor interaction involving the tetrazole group of olmesartan and Gln 257 of the AT 1 receptor. These results suggest that multivalent interactions between an inverse agonist and the AT 1 receptor are required to stabilize the receptor in an inactive conformation in response to the distinct processes that lead to an AngII-independent activation of the Keywords: angiotensin II; cardiac hypertrophy; G protein-coupled receptor; inverse agonist; mechanical stress INTRODUCTIONThe type 1 angiotensin II (AT 1 ) receptor is a member of the G proteincoupled receptor (GPCR) family and mediates most of the actions that angiotensin II (AngII) exerts on the cardiovascular system. 1 AT 1 receptor blockers (ARBs) are non-peptide compounds that selectively bind to the AT 1 receptor and inhibit AngII-induced receptor activation. At present, several ARBs are clinically available as a highly effective and well-tolerated class of drugs for the management of hypertension. In addition, clinical trials have indicated that ARBs provide cardiovascular protection that extends beyond blood pressure lowering. 2 Treatment with ARBs effectively prevents cardiac hypertrophy and improves cardiovascular outcomes in patients with hypertension. 2,3 Structurally, most ARBs have a common biphenyl-tetrazole ring and unique side chains, which contribute to drug-specific differences in their pharmacokinetic and pharmacodynamic proper-

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Cyclic compressive loading activates angiotensin II type 1 receptor in articular chondrocytes and stimulates hypertrophic differentiation through a G‐protein‐dependent pathway

et al. 2018

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Angiotensin II type 1 receptor ( AT 1R) appears to have a mechanosensing function in a number of cell types. The purpose of this study was to examine whether AT 1R expressed in articular chondrocytes is involved in osteoarthritis (OA) progression in vivo and whether cyclic compressive loading activates the AT 1R and stimulates hypertrophic differentiation of chondrocytes in vitro . The relationships between the modified Mankin score for cartilage degeneration and the expression of AT 1R and type X collagen (Col X) were studied in mouse knees with OA induced using the destabilization‐of‐medial‐meniscus model. Cyclic compressive loads were applied to cultured bovine articular chondrocytes in three‐dimensional agarose scaffolds. Expression of Col X and runt‐related transcription factor 2 (Runx2) was analyzed using RT‐PCR and western blotting. We dissected the downstream pathway for intracellular signal transductions of AT 1R including G‐protein‐dependent and G‐protein‐independent pathways. Positive significant correlations between the Mankin score and the rate of AT 1R‐immunopositive cells and between the rates of AT 1R and Col X expression were noted. The expression of Col X and Runx2 was increased by compressive loading but suppressed by addition of olmesartan, an Ang II receptor blocker, to the agarose scaffolds. Compressive loading upregulated the phosphorylation of c‐Jun N‐terminal kinase ( JNK ), Src, and STAT 1, but olmesartan significantly suppressed only JNK phosphorylation. We conclude that AT 1R expressed by articular chondrocytes may be involved in OA progression in vivo . Mechanical stress can activate AT 1R and stimulate hypertrophic differentiation of chondrocytes through the G‐protein‐dependent pathway. AT 1R has a mechanosensing function in chondrocytes and may be a new therapeutic target in OA .

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Conformational switch of angiotensin II type 1 receptor underlying mechanical stress‐induced activation

Cited by 167 publications

References 24 publications

Sympathoinhibition caused by orally administered telmisartan through inhibition of the AT1 receptor in the rostral ventrolateral medulla of hypertensive rats

Sympathoinhibition caused by orally administered telmisartan through inhibition of the AT1 receptor in the rostral ventrolateral medulla of hypertensive rats

Multivalent ligand–receptor interactions elicit inverse agonist activity of AT1 receptor blockers against stretch-induced AT1 receptor activation

Cyclic compressive loading activates angiotensin II type 1 receptor in articular chondrocytes and stimulates hypertrophic differentiation through a G‐protein‐dependent pathway

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