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

Esch, Joep H.M. van; Tom, Beril; Dive, Vincent; Batenburg, Wendy W.; Georgiadis, Dimitris; Yiotakis, Athanasios; Gool, Jeanette M.G. van; Bruijn, R. J.A. de; Vries, René de; Danser, A.H. Jan

doi:10.1161/01.hyp.0000151323.93372.f5

Cited by 56 publications

(47 citation statements)

References 32 publications

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“…This is very different from the N-terminal-inactivated mice, ACE7/7, which had a response to Ang I infusion equivalent to wild-type mice. 11 This observation is also in accordance with a previous publication from van Esch et al 26 They also showed a predominant role of the C-terminus in the in vivo conversion of Ang I to Ang II.…”

Section: Discussionsupporting

confidence: 92%

Angiotensin-Converting Enzyme C-Terminal Catalytic Domain Is the Main Site of Angiotensin I Cleavage In Vivo

et al. 2008

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Abstract-Angiotensin-converting enzyme (ACE) plays a central role in the production of the vasoconstrictor angiotensin II. ACE is a single polypeptide, but it contains 2 homologous and independent catalytic domains, each of which binds zinc. To understand the in vivo role of these 2 domains, we used gene targeting to create mice with point mutations in the ACE C-domain zinc-binding motif. Such mice, termed ACE13/13, produce a full-length ACE protein with tissue expression identical to wild-type mice. Analysis of ACE13/13 mice showed that they produce ACE having only N-domain catalytic activity, as determined by the hydrolysis of domain specific substrates and by chloride sensitivity. ACE13/13 mice have blood pressure and blood angiotensin II levels similar to wild-type mice. However, plasma renin concentration is increased 2.6-fold and blood angiotensin I levels are increased 7.5-fold. Bradykinin peptide levels are not different from wild-type levels. ACE13/13 mice have a reduced increase of blood pressure after intravenous infusion of angiotensin I. ACE13/13 mice have a normal renal structure, but they are not able to concentrate urine after dehydration as effectively as wild-type mice. This study shows that the C-domain of ACE is the predominant site of angiotensin I cleavage in vivo. Although mice lacking C-domain activity have normal physiology under laboratory conditions, they respond less well to the stress of dehydration. (Hypertension. 2008;51:267-274.)

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Section: Discussionsupporting

confidence: 92%

Angiotensin-Converting Enzyme C-Terminal Catalytic Domain Is the Main Site of Angiotensin I Cleavage In Vivo

et al. 2008

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“…The absence of aldosterone-induced vasodilation in HCAs may relate to our inability to observe endothelial NO release in these vessels. 23 Limited NO release could also underlie the absence of a vasodilator response to 17␤-estradiol in HCAs. Despite the higher incidence of stroke, myocardial infarction, and dementia in postmenopausal women taking hormone replacement therapy, 24 virtually all in vitro studies published so far claim that estrogen induces vasodilation through endothelium-dependent or endothelium-independent mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Nongenomic Effects of Aldosterone in the Human Heart

et al. 2005

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Abstract-Aldosterone exerts rapid "nongenomic" effects in various nonrenal tissues. Here, we investigated whether such effects occur in the human heart. Trabeculae and coronary arteries obtained from 57 heart valve donors (25 males; 32 females; 17 to 66 years of age) were mounted in organ baths. Aldosterone decreased contractility in atrial and ventricular trabeculae by maximally 34Ϯ3% and 15Ϯ4%, respectively, within 5 to 15 minutes after its application. The protein kinase C (PKC) inhibitor chelerythrine chloride, but not the mineralocorticoid receptor antagonists spironolactone and eplerenone, blocked this effect. Aldosterone also relaxed trabeculae that were prestimulated with angiotensin II (Ang II), and its negative inotropic effects were mimicked by hydrocortisone (at 10-fold lower potency) but not 17␤-estradiol. Aldosterone concentrations required to reduce inotropy were present in failing but not in normal human hearts. Previous exposure of coronary arteries to 1 mol/L aldosterone or 17␤-estradiol (but not hydrocortisone) doubled the maximum contractile response (E max ) to Ang II. ⌬E max correlated with extracellular signal-regulated kinase (ERK) 1/2 phosphorylation (PϽ0.01). Spironolactone and eplerenone did not block the potentiating effect of aldosterone. Studies in porcine renal arteries showed that potentiation also occurred at pmol/L aldosterone levels but not at 17␤-estradiol levels Ͻ1 mol/L. Aldosterone did not potentiate the ␣ 1 -adrenoceptor agonist phenylephrine. In conclusion, aldosterone induces a negative inotropic response in human trabeculae (thereby antagonizing the positive inotropic actions of Ang II) and potentiates the vasoconstrictor effect of Ang II in coronary arteries. These effects are specific and involve PKC and ERK 1/2, respectively. Furthermore, they occur in a nongenomic manner, and require pathological aldosterone concentrations.

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“…Angiotensin I, although it is an ACE substrate, does not elicit the phosphorylation of ACE on Ser1270 (Kohlstedt et al, 2004) and was also unable to elicit the phosphorylation of MYH9. Because selective inhibition of the C-domain active center of ACE is sufficient to inhibit the conversion of angiotensin I, whereas bradykinin is a substrate for both the N-and C-terminal active centers (van Esch et al, 2005), it is tempting to suggest that angiotensin I does not interact with the appropriate site on ACE to elicit ACE signaling.…”

Section: Myh9 Phosphorylation By Ace Signaling 23mentioning

confidence: 99%

Signaling via the Angiotensin-Converting Enzyme Results in the Phosphorylation of the Nonmuscle Myosin Heavy Chain IIA

Kohlstedt

Kellner²,

Busse³

et al. 2005

Mol Pharmacol

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The phosphorylation of the short C-terminal cytoplasmic domain of the somatic angiotensin-converting enzyme (ACE) is involved in the regulation of enzyme shedding. We determined whether the phosphorylation of the cytoplasmic domain of ACE (ACEct) on Ser1270 regulates the cleavage/secretion of the enzyme by affecting its association with other proteins. ACE was associated with ␤-actin and the nonmuscle myosin heavy chain IIA (MYH9) in endothelial cells, as determined by coimmunoprecipitation experiments as well as an ACEct affinity column. The ACE-associated MYH9 immunoprecipitated from 32 P-labeled endothelial cells was basally phosphorylated and cell stimulation with ACE inhibitors, or with bradykinin, increased the phosphorylation of MYH9. Casein kinase 2 (CK2) but not protein kinase C phosphorylated MYH9 in vitro, CK2 coprecipitated with MYH9 from endothelial cells and the phosphorylation of MYH9 in intact cells paralleled the phosphorylation of ACE on Ser1270 by CK2. The CK2 inhibitor 5,6-dichloro-1-␤-D-ribofuranosylbenzimidazole attenuated the phosphorylation of ACE and MYH9, disrupted their association, and enhanced the cleavage/secretion of ACE from the plasma membrane. Cytochalasin D decreased the interaction between ACE and MYH9 and stimulated ACE shedding. Although MYH9 was still able to associate with residual amounts of a nonphosphorylatable S1270A ACE mutant, no ACE inhibitor-induced increase in MYH9 phosphorylation could be detected in S1270A-expressing cells. These data indicate that the interaction of ACE with MYH9 determines ACE shedding and is modulated by phosphorylation processes. Furthermore, because ACE inhibitors affect the phosphorylation of MYH9, the phosphorylation of this class II myosin might contribute to the phenomenon of ACE signaling in endothelial cells.

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

Cited by 56 publications

References 32 publications

Angiotensin-Converting Enzyme C-Terminal Catalytic Domain Is the Main Site of Angiotensin I Cleavage In Vivo

Angiotensin-Converting Enzyme C-Terminal Catalytic Domain Is the Main Site of Angiotensin I Cleavage In Vivo

Nongenomic Effects of Aldosterone in the Human Heart

Signaling via the Angiotensin-Converting Enzyme Results in the Phosphorylation of the Nonmuscle Myosin Heavy Chain IIA

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