Angiotensin II Type 2 Receptor Gene Transfer Downregulates Angiotensin II Type 1a Receptor in Vascular Smooth Muscle Cells

Jin, Xue-Qing; Fukuda, Noboru; Su, Jin-Zi; Lai, Yimu; Suzuki, Ryo; Tahira, Yoshiko; Takagi, Hidenari; Ikeda, Yukihiro; Kanmatsuse, Katsuo; Miyazaki, Hitoshi

doi:10.1161/01.hyp.0000016179.52601.b4

Cited by 61 publications

(49 citation statements)

References 25 publications

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“…27 Numerous studies have demonstrated that angiotensin II through AT1 receptor induces VSM cell proliferation and hypertrophy and has an essential role in extracellular matrix expansion. [29][30][31][32] Furthermore, Candesartan and cavernous tissue in SHR JE Toblli et al cell culture, animal models and clinical studies have supported the idea that AT1 receptor activation causes vascular superoxide release in vitro and in vivo leading to impairment of endothelium-dependent vasodilation. 33,34 In agreement with these findings, inhibition of AT1 receptor activation by AT1 receptor antagonist or ACE inhibitors improves endothelial dysfunction.…”

Section: Discussionmentioning

confidence: 96%

Candesartan cilexetil protects cavernous tissue in spontaneously hypertensive rats

Toblli

Stella²,

Mazza

et al. 2004

Int J Impot Res

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In previous experiments, our group demonstrated morphological changes in erectile tissue from male spontaneously hypertensive rats (SHR). The present study was performed to determine whether an angiotensin II receptor blocker could protect cavernous tissue (CT) from these structural alterations in SHR. Male SHR and Wistar-Kyoto (WKY) rats were studied during 4 months. Rats were divided into three groups: SHR (n ¼ 10), SHR with candesartan cilexetil (n ¼ 10) and WKY rats (n ¼ 10). Candesartan cilexetil 7.5 mg/kg/day was administered orally throughout the study. CT was processed for pathology studies. The amount of (1) cavernous smooth muscle (CSM), (2) vascular smooth muscle (VSM), (3) collagen type III, and the rat endothelial cell antibody (RECA-1)/tunica media ratio in cavernous arteries were evaluated. SHR with candesartan cilexetil showed a lower blood pressure, a lower percentage of CSM, smaller VSM area, with a higher RECA-1/media ratio, and a lower percentage of collagen type III, when compared to untreated SHR. In addition, SHR showed a positive correlation between systolic blood pressure (SBP) and CSM amount (r ¼ 0.91; Po0.01), and SBP and the percentage of collagen type III (r ¼ 0.88; Po0.01); these correlations were not observed either in SHR treated with candesartan cilexetil or in WKY rats. We conclude that candesartan cilexetil provides a significant protective role against morphologic changes in vessels as well as in cavernous spaces of the erectile tissue, caused by high blood pressure, in SHR.

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Section: Discussionmentioning

confidence: 96%

Candesartan cilexetil protects cavernous tissue in spontaneously hypertensive rats

Toblli

Stella²,

Mazza

et al. 2004

Int J Impot Res

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“…Although we cannot completely rule out that our results are a nuance of receptor overexpression, such an idea (ie, constitutive activity of the AT 2 receptor) has precedence. 31,[42][43][44][45] For example, the AT 2 receptor displays ligand pharmacology consistent with it residing in a constant, active conformation. 43 This receptor induces apoptosis in the absence of Ang II stimulation, and the AT 2 receptor antagonist PD123319 does not modulate this effect.…”

Section: Discussionmentioning

confidence: 99%

“…43 This receptor induces apoptosis in the absence of Ang II stimulation, and the AT 2 receptor antagonist PD123319 does not modulate this effect. 31 In addition, Jin et al 44 showed that overexpression of the AT 2 receptor downregulates AT 1 receptor expression in vascular smooth muscle cells, with and without Ang II stimulation. In contrast to the AT 1 receptor, in which signal transduction pathways are well documented, the extent and type of intracellular signals that emanate from the AT 2 receptor have been difficult to define.…”

Section: Discussionmentioning

confidence: 99%

The Angiotensin II Type 2 Receptor Causes Constitutive Growth of Cardiomyocytes and Does Not Antagonize Angiotensin II Type 1 Receptor–Mediated Hypertrophy

2005

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Abstract-Angiotensin II (Ang II) has important actions on the heart via type 1 (AT 1 ) and type 2 (AT 2 ) receptors. The link between AT 1 receptor activation and the hypertrophy of cardiomyocytes is accepted, whereas the contribution of the AT 2 receptor, which reportedly antagonizes the AT 1 receptor, is contentious. This ambiguity is primarily based on in vivo approaches, in which the direct effect of the AT 2 receptor and its modulation of the AT 1 receptor (at the level of the cardiomyocyte) are difficult to establish. In this study, we used adenoviruses encoding AT 1 and AT 2 to coexpress these receptors in isolated cardiomyocytes, allowing a direct examination of the consequence of varying AT 1 /AT 2 stoichiometry on cardiomyocyte hypertrophy. Key Words: angiotensin II Ⅲ hypertrophy Ⅲ myocytes Ⅲ rats Ⅲ receptors L eft ventricular hypertrophy (LVH) is a major independent risk factor for premature death. 1 Extensive experimental and clinical evidence supports a role for the vasoactive hormone angiotensin II (Ang II) in the development of hypertension and the associated cardiomyocyte enlargement, which is a hallmark of LVH. Ang II binds with high affinity to type 1 (AT 1 ) and type 2 (AT 2 ) Ang II receptors, which are 7-transmembrane spanning, G-protein-coupled receptors. 2 AT 1 receptors are well characterized and mediate the established actions of Ang II, including vasoconstriction, aldosterone and vasopressin release, renal sodium reabsorption, increased collagen deposition, cellular proliferation, and, importantly, cardiomyocyte hypertrophy. The role of the AT 2 receptor is less clear, but current theories favor a role in opposing the actions of the AT 1 receptor. 3-7 AT 2 receptors are highly expressed in the fetus; however, after birth, the AT 2 receptor expression decreases to low levels. 2 In normal, adult human and rat hearts, AT 1 and AT 2 receptors are expressed, 8 -10 and they have been shown to be upregulated during cardiovascular pathologies. 8,9 The specific signaling pathways activated via the AT 2 receptor remain poorly resolved, although AT 2 receptors reportedly inhibit AT 1 receptor signaling pathways, such as extracellular signalregulated kinase 1/2 (ERK1/2) mitogen-activated protein kinases (MAPKs), by activating specific tyrosine or serine/ threonine phosphatases. 6,11,12 More recent evidence suggests functional heterodimerization between the AT 1 and AT 2

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“…However, it has been shown that the different Ang II receptors can influence each other. [36][37][38][39][40] To exclude the possibility that the lack of one of the receptor subtypes alters the properties of the remaining receptors, we also investigated the effects of Ang-(1-7) in mice lacking all three Ang II receptor types. Although Ang-(1-7) was not able to reduce absolute MAP in the hypotensive triple KO mice, the percent changes induced by Ang-(1-7) were comparable with that in WT mice.…”

Section: Impact Ofmentioning

confidence: 99%

Hemodynamic effects of vasorelaxant compounds in mice lacking one, two or all three angiotensin II receptors

et al. 2012

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The renin-angiotensin system (RAS) has a vital role in regulating the cardiovascular system. The primary effector of the RAS is the octapeptide angiotensin (Ang) II, a potent regulator of blood pressure and water homeostasis. Ang II mediates its functions through the stimulation of two distinct receptors, AT 1 (two subtypes in rodents (AT 1a and AT 1b )) and AT 2 . It was shown that in addition to Ang II, shorter fragments of Ang are also biologically active. Ang-(1-7) came into focus because it opposes many of the detrimental effects of Ang II. However, it is still controversial whether Ang II receptors are involved in Ang-(1-7)-mediated signaling. To characterize the impacts of Ang II receptors on Ang-(1-7)-stimulated vascular relaxation, the effects of acute infusion of the three vasorelaxant compounds, that is, Ang-(1-7), bradykinin (BK) and acetylcholine (ACh), on heart rate (HR) and mean arterial pressure (MAP) were investigated in mice deficient for one, two or all three Ang II receptors. Ang-(1-7) and BK reduced MAP in wild-type, AT 1a /AT 1b -deficient and AT 2 -deficient mice. Although the change in absolute MAP values in the hypotensive triple knockouts (KO) could not be further reduced by both peptides, the percent change in MAP was comparable between the triple KO and wild-type mice. Both peptides did not alter the HR in all four genotypes. ACh significantly reduced absolute MAP values in all four genotypes with a similar percentage of reduction. In contrast to Ang-(1-7) and BK, ACh significantly reduced HR without genotypic differences. Our results generate proof that Ang-(1-7)-induced effects on MAP are mediated by a receptor that is independent of AT 1 and AT 2 .

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Angiotensin II Type 2 Receptor Gene Transfer Downregulates Angiotensin II Type 1a Receptor in Vascular Smooth Muscle Cells

Cited by 61 publications

References 25 publications

Candesartan cilexetil protects cavernous tissue in spontaneously hypertensive rats

Candesartan cilexetil protects cavernous tissue in spontaneously hypertensive rats

The Angiotensin II Type 2 Receptor Causes Constitutive Growth of Cardiomyocytes and Does Not Antagonize Angiotensin II Type 1 Receptor–Mediated Hypertrophy

Hemodynamic effects of vasorelaxant compounds in mice lacking one, two or all three angiotensin II receptors

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