Angiotensin-(1–7) Is a Modulator of the Human Renin-Angiotensin System

Roks, Ajm; Geel, PP van; Pinto, YM; Buikema, Hendrik; Henning, Robert H.; Zeeuw, de Dick; Gilst, van Wiekert

doi:10.1161/01.hyp.34.2.296

Cited by 164 publications

(132 citation statements)

References 39 publications

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“…16,18,[25][26][27] Thereby, the increase of ACE2 is a potential reason for the antihypertensive effect of atRA in SHR by attenuating the vasoconstrictive effect of Ang II, promoting the formation of Ang 1-7 and subsequently facilitating the release of NO.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of Angiotensin-Converting Enzyme 2 by All- trans Retinoic Acid in Spontaneously Hypertensive Rats

et al. 2004

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Abstract-There is increasing evidence that all-trans retinoic acid (atRA) influences gene expression of components of renin-angiotensin system (RAS), which plays a pivotal role in the pathophysiology of essential hypertension. To further validate effects of atRA on the RAS and to assess the possibility that atRA affects the activity of angiotensin-converting enzyme 2 (ACE2), gene, and protein expression of ACE2 have been examined by real-time polymerase chain reaction and Western blot methods in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. Rats were treated with atRA (10 or 20 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) or placebo given as daily intraperitoneal injection for 1 month. ACE2 expression was markedly decreased in placebo-treated SHR when compared with WKY rats. However, in atRA-treated SHR, a significant upregulation of ACE2 expression was observed in heart and kidney. In conclusion, chronic atRA treatment increases gene and protein expressions of ACE2, resulting in the reduction of blood pressure and the attenuation of myocardial damage in SHR, which suggests that atRA may be an attractive candidate for the potential prevention and treatment of human essential hypertension. Key Words:hypertension, essential Ⅲ angiotensin-converting enzyme Ⅲ renin-angiotensin system Ⅲ rats I t is well-recognized that essential hypertension is a genetically complex metabolic and cardiovascular disorder controlled by both genetic and environmental factors. 1 The ideal aim of modern antihypertensive therapy is not only a reduction of blood pressure but also the prevention or amelioration of its complications, such as myocardial remodeling at the molecular genetic level. 2,3 Research advances on the key transcription factors and nuclear hormone receptors provide insight into the development of novel transcriptionmodulating antihypertensive drugs, among which is all-trans retinoic acid (atRA), a biologically active metabolite of vitamin A. 2 atRA modulates gene transcription and exerts its other effects by binding the retinoic acid receptor (RAR) and retinoid X receptor (RXR) 4,5 and interfering with some key transcription factors such as the activated protein-1. 6,7 Studies have demonstrated that atRA influences the activities of genes responsible for the pathogenesis of hypertension and its complications. 2,3,6,8 Dechow et al 6 reported that atRA reduced blood pressure in the renal damage model. Spontaneously hypertensive rats (SHR) are recognized as genetically hypertensive rats, which resemble, in many aspects, humans with essential hypertension. 9 Chronic atRA treatment prevented medial thickening of intramyocardial and intrarenal arteries and ventricular fibrosis in SHR. 3 However, whether atRA reduces arterial pressure and attenuates myocardial damage in SHR deserves further study.atRA has been shown to regulate the gene expression of components of renin-angiotensin system (RAS), including renin, angiotensin-converting enzyme (ACE), angiotensin (Ang) II, and its type 1 (AT 1 ) receptor. 6,7,10 RAS is critically inv...

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Section: Discussionmentioning

confidence: 99%

Upregulation of Angiotensin-Converting Enzyme 2 by All- trans Retinoic Acid in Spontaneously Hypertensive Rats

et al. 2004

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“…1 However, it simultaneously reduced the maximum effect of Ang I, and identical observations were made toward Ang II. 19,20 This suggests that the Ang-(1-7) concentrations that selectively block the C-domain are also capable of blocking AT 1 receptors, thereby not allowing us to demonstrate the functional consequence of selective C-domain inhibition by Ang-(1-7) toward Ang I.…”

Section: Discussionmentioning

confidence: 99%

Selective Angiotensin-Converting Enzyme C-Domain Inhibition Is Sufficient to Prevent Angiotensin I–Induced Vasoconstriction

et al. 2005

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Abstract-Somatic angiotensin-converting enzyme (ACE) contains 2 domains (C-domain and N-domain) capable of hydrolyzing angiotensin I (Ang I) and bradykinin. Here we investigated the effect of the selective C-domain and N-domain inhibitors RXPA380 and RXP407 on Ang I-induced vasoconstriction of porcine femoral arteries (PFAs) and bradykinin-induced vasodilation of preconstricted porcine coronary microarteries (PCMAs). Ang I concentrationdependently constricted PFAs. RXPA380, at concentrations Ͼ1 mol/L, shifted the Ang I concentration-response curve (CRC) 10-fold to the right. This was comparable to the maximal shift observed with the ACE inhibitors (ACEi) quinaprilat and captopril. RXP407 did not affect Ang I at concentrations Յ0.1 mmol/L. Bradykinin concentrationdependently relaxed PCMAs. RXPA380 (10 mol/L) and RXP407 (0.1 mmol/L) potentiated bradykinin, both inducing a leftward shift of the bradykinin CRC that equaled Ϸ50% of the maximal shift observed with quinaprilat. Ang I added to blood plasma disappeared with a half life (t 1/2 ) of 42Ϯ3 minutes. Quinaprilat increased the t 1/2 Ϸ4-fold, indicating that 71Ϯ6% of Ang I metabolism was attributable to ACE. RXPA380 (10 mol/L) and RXP407 (0.1 mmol/L) increased the t 1/2 Ϸ2-fold, thereby suggesting that both domains contribute to conversion in plasma. In conclusion, tissue Ang I-II conversion depends exclusively on the ACE C-domain, whereas both domains contribute to conversion by soluble ACE and to bradykinin degradation at tissue sites. Because tissue ACE (and not plasma ACE) determines the hypertensive effects of Ang I, these data not only explain why N-domain inhibition does not affect Ang I-induced vasoconstriction in vivo but also why ACEi exert blood pressure-independent effects at low (C-domain-blocking) doses.

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“…The involvement of AT 1 receptor is in line with studies showing that Ang-(1-7) may either modulate the allosteric binding of Ang II to the AT 1 receptor or compete with Ang II for this binding site. 38,39 For example, in rabbit 39 and human arteries, 40 it has been demonstrated that Ang-(1-7) behaves as a specific noncompetitive antagonist of AT 1 . The involvement of a putative Ang-(1-7) receptor in many actions of this peptide, including the liberation of NO from bovine aortic endothelial cells, 23 was also demonstrated previously.…”

Section: Discussionmentioning

confidence: 99%

Antithrombotic Effect of Captopril and Losartan Is Mediated by Angiotensin-(1-7)

et al. 2002

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Abstract-It is well established that renin-angiotensin system blockers exert NO/prostacyclin-dependent antithrombotic effects. Because some beneficial effects of these drugs are mediated by angiotensin (Ang)-(1-7), in the present study we examined if their antithrombotic action could be mediated by Ang-(1-7). Intravenous infusion of Ang-(1-7) (1, 10, or 100 pmol/kg per minute for 2 hours) into rats developing venous thrombosis caused 50% to 70% reduction of the thrombus weight. This effect was dose-dependently reversed by cotreatment with A-779 (selective Ang- [1][2][3][4][5][6][7] receptor antagonist) or EXP 3174 (angiotensin type 1 receptor antagonist) but not by PD 123,319 (angiotensin type 2 receptor antagonist). Similarly, the antithrombotic effects of captopril (ACE inhibitor) and losartan (angiotensin type 1 receptor blocker) were attenuated by A-779 in a dose-dependent manner. The effect of Ang-(1-7) was completely abolished by concomitant administration of NO synthase inhibitor (N G -nitro-L-arginine methyl ester) and prostacyclin synthesis inhibitor (indomethacin), as has been shown previously for captopril and losartan. Thus, the antithrombotic effect of renin-angiotensin system blockers involves Ang-(1-7)-evoked release of NO and prostacyclin. (Hypertension. 2002;40:774-779.)

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Angiotensin-(1–7) Is a Modulator of the Human Renin-Angiotensin System

Cited by 164 publications

References 39 publications

Upregulation of Angiotensin-Converting Enzyme 2 by All- trans Retinoic Acid in Spontaneously Hypertensive Rats

Upregulation of Angiotensin-Converting Enzyme 2 by All- trans Retinoic Acid in Spontaneously Hypertensive Rats

Selective Angiotensin-Converting Enzyme C-Domain Inhibition Is Sufficient to Prevent Angiotensin I–Induced Vasoconstriction

Antithrombotic Effect of Captopril and Losartan Is Mediated by Angiotensin-(1-7)

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