Effect of angiotensin-converting enzyme or vasopeptidase inhibition on ventricular size and function in patients with heart failure: The Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE) echocardiographic study

Solomon, Scott D.; Skali, Hicham; Bourgoun, Mikhail; Fang, James C.; Ghali, Jalal K.; Martelet, Michel; Wojciechowski, Dariusz; Ansmite, Baiba; Skards, J.; Laks, Toivo; Henry, David; Packer, Milton; Pfeffer, Marc A.

doi:10.1016/j.ahj.2004.09.056

Cited by 42 publications

(15 citation statements)

References 21 publications

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“…For a negative control, we fused ACE to B 2 receptors and expressed them as a single protein molecule in CHO cells. Results of our experiments established the association of B 2 receptors and ACE on the plasma membrane and indicate a mode of action of ACE inhibitors that may contribute to their successful therapeutic effects (7)(8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 58%

“…Fetal bovine serum was from Atlanta Biologicals (Norcross, GA). [5,6,8,9,11,12,14, Arg-Pro-Pro-Gly-Phe-Ser-Pro-Pheψ[CH 2 NH]Arg) was from EMD Biosciences (La Jolla, CA), Hippuryl-His-Leu (Hip-His-Leu) was from Bachem (Philadelphia, PA). Alexa 568 conjugate and anti-GFP serum were from Molecular Probes (Eugene, Oregon).…”

Section: Methodsmentioning

confidence: 99%

“…These two peptide substrates of ACE, Ang I and bradykinin, frequently have opposing actions on the cardiovascular system. Millions of patients receive ACE inhibitors to treat conditions such as congestive heart failure or diabetic nephropathy, besides hypertension (7)(8)(9)(10)(11)(12). The beneficial effects of ACE inhibition on the heart and blood vessels are at least partly mediated by kinins acting via bradykinin B 2 receptors, because ACE inhibition reduces kinin degradation (13,14), but ACE inhibitors have other favorable actions as well.…”

Section: Introductionmentioning

confidence: 99%

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Human ACE and bradykinin B ₂ receptors form a complex at the plasma membrane

et al. 2006

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To investigate how angiotensin-I converting enzyme (ACE) inhibitors enhance the actions of bradykinin (BK) on B 2 receptors independent of blocking BK inactivation, we expressed human somatic ACE and B 2 receptors in CHO cells. Bradykinin and its ACE-resistant analogue were the receptor agonists. B 2 fused with green fluorescent protein (GFP) and ACE were coprecipitated with antisera to GFP or ACE shown in Western blots. Immunohistochemistry of fixed cells localized ACE by red color and B 2 -GFP by green. Yellow color on plasma membranes of coexpressing cells also indicated enzyme-receptor complex formation. Using ACE-fused cyan fluorescent protein donor and B 2 -fused yellow fluorescent protein acceptor, we registered fluorescence resonance energy transfer (FRET) by the enhanced fluorescence of donor upon acceptor photo-bleaching, establishing close (within 10 nm) positions of B 2 receptors and ACE. Bradykinin stimulation cointernalized ACE and B 2 receptors. We expressed ACE fused to N-terminus of B 2 receptors, anchoring only receptors to plasma membranes. Here, in contrast to cells where both ACE and B 2 receptors are separately anchored, ACE inhibitors neither enhance activation of chimeric B 2 , nor resensitize desensitized B 2 receptors. Heterodimer formation between ACE and B 2 receptors can be a mechanism for ACE inhibitors to augment kinin activity at cellular level.

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Section: Introductionmentioning

confidence: 58%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Human ACE and bradykinin B ₂ receptors form a complex at the plasma membrane

et al. 2006

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“…[27][28][29][30] ACE is known to hydrolyze a number of peptides, and the therapeutic effects of ACEi have been attributed mainly to inhibition of both conversion of Ang I to II and kinin hydrolysis. Recently we showed that another peptide, Ac-SDKP, has antifibrotic effects on the heart and kidney 10,11 and mediates some of the effects of ACEi in hearts of hypertensive rats, 31 because ACEi prevented degradation of endogenous Ac-SDKP and significantly raised its circulating levels in Ang II-induced hypertension.…”

Section: Discussionmentioning

confidence: 99%

Role of N-Acetyl-Seryl-Aspartyl-Lysyl-Proline in the Antifibrotic and Anti-Inflammatory Effects of the Angiotensin-Converting Enzyme Inhibitor Captopril in Hypertension

et al. 2007

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Abstract-Angiotensin-converting enzyme inhibitors (ACEis) are known to have antifibrotic effects on the heart and kidney in both animal models and humans. N-acetyl-seryl-aspartyl-lysyl-proline is a natural inhibitor of proliferation of hematopoietic stem cells and a natural substrate of ACEi that was reported to prevent cardiac and renal fibrosis in vivo. However, it is not clear whether N-acetyl-seryl-aspartyl-lysyl-proline participates in the antifibrotic effects of ACEi. To clarify this issue, we used a model of aldosterone-salt-induced hypertension in rats treated with the ACEi captopril either alone or combined with an anti-N-acetyl-seryl-aspartyl-lysyl-proline monoclonal antibody. These hypertensive rats had the following: (1) left ventricular and renal hypertrophy, as well as increased collagen deposition in the left ventricular and the kidney; (2) glomerular matrix expansion; and (3) increased ED1-positive cells and enhanced phosphorylated-p42/44 mitogen-activated protein kinase in the left ventricle and kidney. The ACEi alone significantly lowered systolic blood pressure (Pϭ0.008) with no effect on organ hypertrophy; it significantly lowered left ventricular collagen content, and this effect was blocked by the monoclonal antibody as confirmed by the histological data. As expected, the ACEi significantly decreased renal collagen deposition and glomerular matrix expansion, and these effects were attenuated by the monoclonal antibody. Likewise, the ACEi significantly decreased ED1-positive cells and inhibited p42/44 mitogen-activated protein kinase phosphorylation in the left ventricle and kidney, and these effects were blocked by the monoclonal antibody. We concluded that in aldosterone-salt-induced hypertension, the antifibrotic effect of ACEi on the heart and kidney, is partially mediated by N-acetyl-seryl-aspartyl-lysyl-proline, resulting in decreased inflammatory cell infiltration and p42/44 mitogen-activated protein kinase activation. Key Words: aldosterone-salt Ⅲ hypertension Ⅲ angiotensin-converting enzyme inhibitor Ⅲ Ac-SDKP Ⅲ collagen Ⅲ mitogen-activated protein kinase Ⅲ macrophage/monocyte infiltration A ngiotensin (Ang)-converting enzyme (ACE) inhibitors (ACEis) are important agents for treatment of hypertension, heart failure, and other cardiovascular and renal diseases. In vivo studies showed that ACEi significantly attenuated cardiac fibrosis in rats with heart failure induced by myocardial infarction, 1 spontaneously hypertensive rats, 2 and rats with aldosterone (ALDO)-salt hypertension 3 and also prevented both cardiac and renal fibrosis in mice given deoxycorticosterone acetate-salt. 4 N-acetyl-seryl-aspartyllysyl-proline (Ac-SDKP), a natural inhibitor of hematopoietic stem cell proliferation and a natural substrate of ACEi, 5,6 was reported to inhibit rat cardiac fibroblast proliferation and collagen synthesis 7,8 and mesangial cell proliferation. 9 It also prevented left ventricular (LV) and renal fibrosis in hypertensive rats, 10,11 as well as renal insufficiency and fibrosis in diabe...

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“…26 However, more recently, the results of the omapatrilat versus enalapril randomized Trial of utility in reducing Events (OVERTURE) trial did not show a difference in the magnitude of improvement in ventricular size or function after 1 year when comparing omapatrilat to enalapril treatment in 321 patients with heart failure (NHHA classification II or more). 27,28 The Omapatrilat in Persons with Enhanced Risk of Atherosclerotic Events (OPERA) was planned to specifically investigate patients with high cardiovascular risk aged above 65 years and with hypertension, 29 however, was abandoned due to insufficient recruiting.…”

Section: Clinical Evidence For a Superior Cardiovascular Effect Of Acmentioning

confidence: 99%

Dual ACE/NEP inhibitors – more than playing the ACE card

Jandeleit‐Dahm¹

2006

J Hum Hypertens

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Effect of angiotensin-converting enzyme or vasopeptidase inhibition on ventricular size and function in patients with heart failure: The Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE) echocardiographic study

Cited by 42 publications

References 21 publications

Human ACE and bradykinin B ₂ receptors form a complex at the plasma membrane

Human ACE and bradykinin B ₂ receptors form a complex at the plasma membrane

Role of N-Acetyl-Seryl-Aspartyl-Lysyl-Proline in the Antifibrotic and Anti-Inflammatory Effects of the Angiotensin-Converting Enzyme Inhibitor Captopril in Hypertension

Dual ACE/NEP inhibitors – more than playing the ACE card

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Effect of angiotensin-converting enzyme or vasopeptidase inhibition on ventricular size and function in patients with heart failure: The Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE) echocardiographic study

Cited by 42 publications

References 21 publications

Human ACE and bradykinin B 2 receptors form a complex at the plasma membrane

Human ACE and bradykinin B 2 receptors form a complex at the plasma membrane

Role of N-Acetyl-Seryl-Aspartyl-Lysyl-Proline in the Antifibrotic and Anti-Inflammatory Effects of the Angiotensin-Converting Enzyme Inhibitor Captopril in Hypertension

Dual ACE/NEP inhibitors – more than playing the ACE card

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Human ACE and bradykinin B ₂ receptors form a complex at the plasma membrane

Human ACE and bradykinin B ₂ receptors form a complex at the plasma membrane