Protective effects of sulfhydryl-containing angiotensin converting enzyme inhibitors against free radical injury in endothelial cells

Mak, I. Tong; Freedman, Alan M.; Dickens, Benjamin F.; Weglicki, William B.

doi:10.1016/0006-2952(90)90250-o

Cited by 102 publications

(51 citation statements)

References 20 publications

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“…A similar mechanism has been suggested for the effects of probucol and its analogues (30) and the antioxidant butylated hydroxytoluNumerous factors have been implicated in the initiation and development of atherosclerotic plaques, including hyperten- ene ( 31 ). However, the data presented here show reduced lesions in animals treated with enalapril, which, unlike captopril, is not capable ofinhibiting free radical-induced lipid peroxidation ( 18) or scavenging oxygen-derived free radicals ( 19), thus indicating that antioxidant activity is not necessary for ACE inhibitors to reduce plaque formation. Similarly, other sulfhydryl-related effects of captopril, such as those observed in cultured endothelial cells (32), also do not necessarily play a role in the attenuation ofatherogenesis by converting enzyme inhibitors.…”

Section: Introductionsupporting

confidence: 80%

“…This model has the advantage that both hypercholesterolemia and drug treatment can be initiated simultaneously, thus allowing one to evaluate drug effects during the early stages of lesion development. Enalapril is useful because it blocks the RAS by the same mechanism as captopril ( 17), although it lacks a sulfhydryl group and the associated antioxidant activity ( 18,19). It has also been shown that in normotensive, cholesterol-fed rabbits enalapril has little or no effect on either blood pressure or lipid profiles (20 Atherosclerosis.…”

Section: Introductionmentioning

confidence: 99%

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Differential effects of renin-angiotensin system blockade on atherogenesis in cholesterol-fed rabbits.

Schuh¹,

Blehm²,

Frierdich³

et al. 1993

J. Clin. Invest.

106

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To investigate the mechanism by which angiotensin-converting enzyme (ACE) inhibition attenuates atherogenesis, we have studied the effects of a nonsulfhydryl ACE inhibitor, enalapril, and an angiotensin receptor antagonist, SC-51316, in cholesterol-fed rabbits. After 3 mo of enalapril treatment (10 mg/kg per d, p.o.) the percent plaque areas in the thoracic aortas of treated animals were significantly reduced (controls: 86.8±3.5%; treated: 31.1±8%, P < 0.001). Aortic cholesterol content was also reduced (controls: 31.4±3.2 mg/g tissue; treated: 7.4±1.8 mg/g, P < 0.001). Enalapril had no significant effect on plasma lipid levels or conscious blood pressure. In a second study, the angiotensin II receptor antagonist SC-51316 was administered at a dose equivalent to enalapril at blocking angiotensin pressor effects in vivo (30 mg/kg per d, p.o.). Evaluation after 3 mo indicated no significant attenuation of aortic atherosclerosis. These results demonstrate that: (a) enalapril attenuates atherogenesis without affecting either blood pressure or plasma lipid levels; (b) antioxidant activity, found with sulfhydryl-containing ACE inhibitors, is not necessary for reducing plaque formation; and (c) the attenuation of atherogenesis by ACE inhibition may not be due to blockade of the renin-angiotensin system. Alternatively, one must consider the multiple effects of ACE inhibition on other hormone systems, such as bradykinin, or the possibility that alternate angiotensin II receptors may be involved in atherosclerosis. (J. Clin.

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Section: Introductionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Differential effects of renin-angiotensin system blockade on atherogenesis in cholesterol-fed rabbits.

Schuh¹,

Blehm²,

Frierdich³

et al. 1993

J. Clin. Invest.

106

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“…This concept is also grounded on a number of experimental evidences accrued through a variety of approaches including animal disease models, in vitro endothelial cell culture, and studies on intracellular signaling pathways. Among the examples, the restoration of impaired homeostasis to vasoactive agents, the reversal of endothelial damage caused by free radicals (Mak et al, 1990;Fujita et al, 2000) or cytotoxic agents (Tokudome et al, 2000;Sacco et al, 2001).…”

mentioning

confidence: 99%

Fibroblast Growth Factor-2 Mediates Angiotensin-Converting Enzyme Inhibitor-Induced Angiogenesis in Coronary Endothelium

Donnini¹,

Solito²,

Giachetti³

et al. 2006

J Pharmacol Exp Ther

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The beneficial effect exerted by angiotensin-converting enzyme inhibitors (ACEI) on vascular endothelium has been attributed to restoration of endothelial cell survival properties and improvement of angiogenesis. Fibroblast growth factor (FGF)-2 is an angiogenic factor for the microvascular endothelium, which tonically promotes endothelial cell growth and survival through an autocrine/ paracrine mechanism. Here, we formulate the hypothesis that FGF-2 might contribute to the prosurvival/proangiogenic effect of ACEI. We investigated zofenoprilat and, in selected experiments, lisinopril, as representatives of ACEI. These compounds induced formation of pseudocapillaries in vessel fragments isolated from porcine coronary and human umbilical arteries by increasing endothelial cell growth up to 5-fold. Angiogenesis was abolished by inhibitors of nitric-oxide synthase (NOS) pathway and by anti-FGF-2 antibodies. Consistently, in cultured coronary endothelial cells (CVECs), ACEI up-regulated endothelial NOS (eNOS) and FGF-2 and induced mitogen-activated protein kinase extracellular signal-regulated kinase 1/2 activation. The overexpression of eNOS/FGF-2 produced, at the functional level, enhanced cell proliferation and migration, the latter effect being dose-dependent and maximal at 0.1 M zofenoprilat. The importance of FGF-2 for the acquisition of the angiogenic phenotype elicited by ACEI was clearly demonstrated by the impairment of endothelial functions following transfection of CVECs with small interference RNA for FGF-2. Moreover, FGF-2 silencing greatly affected the nuclear translocation of the FGF receptor (FGFR)-1, highlighting the autocrine mode of action of FGF-2. At the endothelial membrane level, zofenoprilat appeared to activate the bradykinin B1 receptor, a known stimulant of FGF-2 expression. In conclusion, we show that ACEI exert protective/proangiogenic effects in microvascular coronary endothelial cells by activating the endogenous FGF-2/ FGFR-1 system.

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“…To explain the beneficial effects of RAS blockers during ischemia/reperfusion in WT-p90RSK-Tg hearts that lack angiotensinogen (as opposed to the lack of effect of these drugs in NLC hearts, in which angiotensinogen washout occurred more slowly), the radical-scavenging properties of sulfhydryl-containing angiotensin-converting enzyme inhibitors (like captopril) 4 and the antiarrhythmic (non-Ang II type 1 receptor-mediated) effects of Ang II type 1 receptor antagonists 5 should be taken into consideration. Finally, direct angiotensinogen-Ang II conversion by PRECE, as suggested by the authors, seems unlikely, given the undetectable angiotensin levels in hearts of nephrectomized animals in vivo.…”

Section: To the Editormentioning

confidence: 99%

Letter by Krop et al Regarding Article, “Role of p90 Ribosomal S6 Kinase-Mediated Prorenin-Converting Enzyme in Ischemic and Diabetic Myocardium”

2006

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Protective effects of sulfhydryl-containing angiotensin converting enzyme inhibitors against free radical injury in endothelial cells

Cited by 102 publications

References 20 publications

Differential effects of renin-angiotensin system blockade on atherogenesis in cholesterol-fed rabbits.

Differential effects of renin-angiotensin system blockade on atherogenesis in cholesterol-fed rabbits.

Fibroblast Growth Factor-2 Mediates Angiotensin-Converting Enzyme Inhibitor-Induced Angiogenesis in Coronary Endothelium

Letter by Krop et al Regarding Article, “Role of p90 Ribosomal S6 Kinase-Mediated Prorenin-Converting Enzyme in Ischemic and Diabetic Myocardium”

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