Remodeling of myocardium and arteries by chronic angiotensin converting enzyme inhibition in hypertensive patients

Schartl, M.; Bocksch, Wolfgang; Dreysse, Stefan; Beckmann, Stephan; Franke, Oliver; H??nten, Ursula

doi:10.1097/00004872-199407030-00006

Cited by 27 publications

(22 citation statements)

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“…ACE inhibitors, such as ramiprilat, exert beneficial effects on endothelial function and vascular remodeling (19,25) as well as protect against the progression of atherosclerosis and the occurrence of cardiovascular events in humans (11) (FIG- URE 1). Although the beneficial effects of ACE inhibitors are generally attributed to a decrease in the ACEmediated generation of angiotensin II and the accumulation of bradykinin (30), a number of the effects of this class of compounds cannot be accounted for by inhibition of the enzyme per se.…”

Section: The Evidence For An Ace Signaling Pathwaymentioning

confidence: 99%

New fACEs to the Renin-Angiotensin System

2005

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Inhibition of the angiotensin-converting enzyme (ACE) protects against the progression of several cardiovascular diseases. Recent evidence suggests that some of the beneficial effects of ACE inhibitors can be attributed to the activation of a distinct ACE signaling cascade rather than to the changes in angiotensin II and bradykinin levels. Moreover, at least one other ACE homolog (ACE2) plays a significant role in the regulation of heart and kidney function.

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Section: The Evidence For An Ace Signaling Pathwaymentioning

confidence: 99%

New fACEs to the Renin-Angiotensin System

2005

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“…Quinapril decreased PWV, left ventricular hypertrophy and iliac intimal medial thickness independently of the BP reduction in a six-month study of hypertensive subjects. 48 Antihypertensive doses of perindopril, but not hydralazine, were shown to prevent chronic accumulation of aortic collagen. The collagen reduction was noticed with non-hypertensive doses of perindopril and paralleled the decrease in ACE-activity measured in the aorta tissue but not in the plasma of rats.…”

Section: Ace Inhibitorsmentioning

confidence: 99%

Review: Arterial stiffness and the renin-angiotensin-aldosterone system

Mahmud

Feely

2004

J Renin Angiotensin Aldosterone Syst

113

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Arterial stiffness has recently been recognised as an independent risk factor for cardiovascular morbidity and mortality in hypertension. Many of the complications seen with angiotensin II (Ang II) excess or hyperaldosteronism -an increased event rate, left ventricular hypertrophy, endothelial dysfunction and target organ damage -are also associated with arterial stiffness. It is possible that reduced arterial compliance may be one mechanism whereby increased activity of the renin-angiotensin-aldosterone system (RAAS) produces adverse vascular effects. Common pathophysiological processes, altered collagen turnover and increased fibrosis may underlie both arterial stiffness and RAAS-associated vascular damage.While it is recognised that patients with hyperaldosteronism have increased arterial stiffness, the role of the RAAS in modulating arterial compliance in essential hypertension and in normotensive subjects is less clear cut. There is, however, more consistent data which show that drugs that interfere with Ang II or aldosterone, namely angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and aldosterone antagonists, all reduce arterial stiffness. In many cases, this is to a greater extent than predicted from the extent of reduction in blood pressure (BP), suggesting a role for RAAS in vascular stiffness in hypertensive subjects. There is also evidence that combined ACE inhibitors (ACE-Is) and ARBs may have an additive effect in reducing stiffness. The reduction in cardiovascular mortality in end-stage renal disease patients treated with ACE-Is was preferentially seen in those who had reduced arterial stiffness. These data suggest that, in addition to regulation of vascular biology and BP, the RAAS is an important determinant of arterial stiffness in health and, more particularly, in disease. IntroductionThe pulse has retained a central role throughout the history of medicine. It was, however, more an art than a science until the 19th century, when sphygmography provided the first graphic recordings of the arterial pressure pulse. Abnormalities in the pulse wave contour were considered indicative of stiff arteries and subsequently used to diagnose hypertension and Bright's disease.About the same time as Tigerstedt and Bergman discovered renin, sphygmography was abandoned in favour of cuff sphygmomanometry. There has been a recent awakening in the field of arterial stiffness follow-

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“…Antisense oligonucleotides against ACE, in contrast, are reported to prevent neointimal formation after balloon angioplasty (Morishita et al, 2000), and ACE inhibitors decrease vascular hypertrophy in hypertensive animals (Clozel et al, 1991). Furthermore, ACE inhibitors, such as ramiprilat, exert beneficial effects on endothelial function and vascular remodeling (Schartl et al, 1994;Mancini et al, 1996) and protect against the progression of atherosclerosis and the occurrence of cardiovascular events in humans (Heart Outcomes Prevention Evaluation Study Investigators, 2000).…”

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confidence: 99%

Angiotensin-Converting Enzyme (ACE) Dimerization Is the Initial Step in the ACE Inhibitor-Induced ACE Signaling Cascade in Endothelial Cells

Kohlstedt

Gershome²,

Friedrich³

et al. 2006

Mol Pharmacol

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The binding of angiotensin-converting enzyme (ACE) inhibitors to ACE initiates a signaling cascade that involves the phosphorylation of the enzyme on Ser1270 as well as activation of the c-Jun NH 2 -terminal kinase (JNK) and leads to alterations in gene expression. To clarify how ACE inhibitors activate this pathway, we determined their effect on the ability of the enzyme to dimerize and the role of ACE dimerization in the initiation of the ACE signaling cascade. In endothelial cells, ACE was detected as a monomer as well as a dimer in native gel electrophoresis and dimerization/oligomerization was confirmed using the split-ubiquitin assay in yeast. ACE inhibitors elicited a rapid, concentration-dependent increase in the dimer/ monomer ratio that correlated with that of the ACE inhibitorinduced phosphorylation of ACE. Cell treatment with galactose and glucose to prevent the putative lectin-mediated self-association of ACE or with specific antibodies shielding the N terminus of ACE failed to affect either the basal or the ACE inhibitor-induced dimerization of the enzyme. In ACE-expressing Chinese hamster ovary cells, ACE inhibitors elicited ACE dimerization and phosphorylation as well as the activation of JNK with similar kinetics to those observed in endothelial cells. However, these effects were prevented by the mutation of the essential Zn 2ϩ -complexing histidines in the C-terminal active site of the enzyme. Mutation of the N-terminal active site of ACE was without effect. Together, our data suggest that ACE inhibitors can initiate the ACE signaling pathway by inducing ACE dimerization, most probably via the C-terminal active site of the enzyme.Two isoforms of the angiotensin-converting enzyme (ACE) exist in mammals: somatic or tissue ACE and testicular ACE. These enzymes are both type I transmembrane proteins consisting of an extended extracellular domain and a short cytoplasmic tail and are derived from a single gene by virtue of alternative use of transcription initiation sites (Hubert et al., 1991). The extracellular portion of testicular ACE has one active site, whereas that of somatic ACE has two active sites (the N and C domains), each of which contains the amino acid sequence HEMGH that is crucial for Zn 2ϩ binding (Wei et al., 1991). Soluble forms of ACE can also be detected in plasma and other body fluids and are generated by the enzymatic cleavage of the C-terminal extracellular portion, in the socalled juxtamembrane stalk region. All of the ACE isoforms hydrolyze circulating peptides and catalyze the extracellular conversion of the decapeptide angiotensin I to the octapeptide angiotensin II, which is a potent vasopressor. ACE also inactivates the vasodilator peptides bradykinin and kallidin, which are derived from kininogen by the action of kallikreins (for review, see Bernstein et al., 2005). Inhibition of ACE is expected to prevent the formation of angiotensin II and to potentiate the hypotensive response to bradykinin, which would lead to the lowering of blood pressure. Somatic ACE also...

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Remodeling of myocardium and arteries by chronic angiotensin converting enzyme inhibition in hypertensive patients

Cited by 27 publications

References 0 publications

New fACEs to the Renin-Angiotensin System

New fACEs to the Renin-Angiotensin System

Review: Arterial stiffness and the renin-angiotensin-aldosterone system

Angiotensin-Converting Enzyme (ACE) Dimerization Is the Initial Step in the ACE Inhibitor-Induced ACE Signaling Cascade in Endothelial Cells

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