Effect of Chronic Treatment With the Inducible Nitric Oxide Synthase Inhibitor
            <i>N</i>
            -Iminoethyl-
            <scp>l</scp>
            -Lysine or With
            <scp>l</scp>
            -Arginine on Progression of Coronary and Aortic Atherosclerosis in Hypercholesterolemic Rabbits

Behr‐Roussel, Delphine; Rupin, Alain; Simonet, Serge; Bonhomme, Edith; Coumailleau, Sophie; Cordi, Alex; Serkiz, Bernard; Fabiani, Jean‐Noël; Verbeuren, Tony J.

doi:10.1161/01.cir.102.9.1033

Cited by 72 publications

(37 citation statements)

References 41 publications

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“…In contrast, midterm therapy with Los (MI 35 ϩLos [15] ) did not cause a shift in the diastolic pressurevolume curve compared with MI, attenuated the impairment of LVDP and did not modify the scar collagen content. Finally, we observed that midterm and early short-term therapy with los (MI 35 ϩ Los [15] and MI 35 ϩ Los [0][1][2][3][4] ) reduced mortality at 35 days post-MI.…”

Section: Discussionmentioning

confidence: 84%

“…The survival rate was significantly lower in MI 35 and MI 35 ϩ Los [0] groups (P ϭ 0.019 and P ϭ 0.004 vs. the sham group). No differences were found in the MI 35 ϩ Los [15] and MI 35 ϩ Los [0][1][2][3][4] groups. At 56 days, the survival rate was reduced in the MI 56 group (P ϭ 0.017 vs. the sham group).…”

Section: Resultsmentioning

confidence: 99%

“…In our study, most of rabbits with MI died within the first 2 wk, in accordance with the increase in ANG II levels in the plasma and MI zone. Therefore, the fact that early long-term treatment with Los (MI 35 ϩLos [0] ) increased mortality within this period of time in which plasma and infarct zone ANG II levels were increased and the fact that this was not observed in any other treated groups (MI 35 ϩ Los [0][1][2][3][4] , MI 35 ϩ Los [15] , and MI 56 ϩ Los [15] ) suggest that ANG II blockade with Los in MI rabbits is detrimental for survival. This first conclusion may be strengthened by the fact that early shortterm treatment with Los significantly reduced neutrophils, RAM 11-positive macrophages, and CD45 RO-positive lymphocytes at 4 days post-MI, whereas long-term therapy delayed the healing process, as determined by the persistency of these inflammatory cells and the reduction of collagen content at 35 days.…”

Section: Discussionmentioning

confidence: 99%

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Effect of early versus late AT₁ receptor blockade with losartan on postmyocardial infarction ventricular remodeling in rabbits

Gónzalez¹,

Seropián²,

Krieger³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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González GE, Seropian IM, Krieger ML, Palleiro J, Lopez Verrilli MA, Gironacci MM, Cavallero S, Wilensky L, Tomasi VH, Gelpi RJ, Morales C. Effect of early versus late AT1 receptor blockade with losartan on postmyocardial infarction ventricular remodeling in rabbits. Am J Physiol Heart Circ Physiol 297: H375-H386, 2009. First published May 8, 2009 doi:10.1152/ajpheart.00498.2007.-To characterize the temporal activation of the renin-angiotensin system after myocardial infarction (MI) in rabbits, we examined cardiac ANG II type 1 receptor (AT1R) expression and ANG II levels from 3 h to 35 days. The effects of losartan (12.5 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) on functional and histomorphometric parameters when treatment was initiated early (3 h) and late (day 15) post-MI and maintained for different periods of time [short term (4 days), midterm (20 days), and long term (35 days)] were also studied. AT1R expression increased in the MI zone at 15 and 35 days (P Ͻ 0.05). ANG II levels increased (P Ͻ 0.05) in the non-MI zone at 24 h and in the MI zone as well as in plasma at 4 days and then progressively decreased until 35 days. The survival rate was significantly lower in untreated MI and early long-term-treated animals. Diastolic pressure-volume curves in MI at 35 and 56 days shifted to the right (P Ͻ 0.05). This shift was even more pronounced in long-term-treated groups (P Ͻ 0.05). Contractility decreased (P Ͻ 0.05 vs. sham) in the untreated and long-term-treated groups and was attenuated in the midterm-treated group. The early administration of losartan reduced RAM 11-positive macrophages from 4.15 Ϯ 0.05 to 3.05 Ϯ 0.02 cells/high-power field (HPF; P Ͻ 0.05) and CD45 RO-positive lymphocytes from 2.23 Ϯ 0.05 to 1.48 Ϯ 0.01 cells/HPF (P Ͻ 0.05) in the MI zone at 4 days. Long-term treatment reduced the scar collagen (MI: 70.50 Ϯ 2.35% and MI ϩ losartan: 57.50 Ϯ 2.48, P Ͻ 0.05), determined the persistency of RAM 11-positive macrophages (3.02 Ϯ 0.13 cells/HPF) and CD45 RO-positive lymphocytes (2.77 Ϯ 0.58 cells/HPF, P Ͻ 0.05 vs. MI), and reduced the scar thinning ratio at 35 days (P Ͻ 0.05). Consequently, the temporal expressions of cardiac AT1R and ANG II post-MI in rabbits are different from those described in other species. Long-term treatment unfavorably modified post-MI remodeling, whereas midterm treatment attenuated this harmful effect. The delay in wound healing (early reduction and late persistency of inflammatory infiltrate) and adverse remodeling observed in long-term-treated animals might explain the unfavorable effect observed in rabbits.angiotensin II type 1 receptor blockers MYOCARDIAL INFARCTION (MI) leads to global structural alterations that involve infarcted as well as noninfarcted areas in a process collectively known as ventricular remodeling (26). The initial phase of remodeling, which starts in the acute phase of the MI, is associated with geometric changes and dilation of the MI zone, as a consequence of injured wall thinning (14, 26). Shortly afterward, this dilation may progress to the whole ventricle, and...

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Section: Discussionmentioning

confidence: 84%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Effect of early versus late AT₁ receptor blockade with losartan on postmyocardial infarction ventricular remodeling in rabbits

Gónzalez¹,

Seropián²,

Krieger³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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“…We previously demonstrated that endoglin is expressed by the aortic vessel endothelium in normo-and hypercholesterolemic mice 6,7) . Moreover, endoglin expression was also detected in human and porcine atherosclerotic lesions 3,4,8) .…”

Section: Introductionmentioning

confidence: 90%

Atorvastatin Increases Endoglin, SMAD2, Phosphorylated SMAD2/3 and eNOS Expression in ApoE/LDLR Double Knockout Mice

Nachtigal

Pospisilova

Vecerova

et al. 2009

JAT

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Aim: Endoglin is a homodimeric transmembrane glycoprotein that has been demonstrated to affect transforming growth factor (TGF-) signaling and endothelial nitric oxide synthase (eNOS) expression by affecting SMAD proteins in vitro. Thus, in this study we stepped forward to elucidate whether endoglin is co-expressed with SMAD2, phosphorylated SMAD2/3 proteins and eNOS in vivo in atherosclerotic lesions in ApoE/LDLR double knockout mice. In addition, we sought whether endoglin expression as well as the expression of SMAD2, phosphorylated SMAD2/3 and eNOS is affected by atorvastatin treatment. Methods: Two-month-old female ApoE/LDLR double knockout mice were divided into two groups. The control group was fed with the western type diet whereas in the atorvastatin group, atorvastatin at dose 100 mg/kg per day was added to the same diet. Immunohistochemical and western blot analysis of endoglin, SMAD2, phosphorylated SMAD2/3 and eNOS expressions in aorta were performed.

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“…The significance of ONOO − -driven modifications is underscored by the implication of both NADPH oxidase (a source of O2 •− ) [10,26,27] and eNOS (a source of • NO) [28] activities in vascular endothelial dysfunction and by the fast reaction of O2 •− and • NO to yield ONOO − .…”

Section: Introductionmentioning

confidence: 99%

LDL protein nitration: Implication for LDL protein unfolding

Hamilton

Asatryan

Nilsen

et al. 2008

Archives of Biochemistry and Biophysics

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Oxidatively-or enzymatically-modified low-density lipoprotein (LDL) is intimately involved in the initiation and progression of atherosclerosis. The in vivo modified LDL is electro-negative (LDL − ) and consists of peroxidized lipid and unfolded ApoB-100 protein. This study was aimed at establishing specific protein modifications and conformational changes in LDL − assessed by liquid chromatography/tandem mass spectrometry (LC/MS/MS) and circular dichroism analyses, respectively. The functional significance of these chemical modifications and structural changes were validated with binding and uptake experiments to-and by bovine aortic endothelial cells (BAEC).The plasma LDL − fraction showed increased nitrotyrosine and lipid peroxide content as well as a greater cysteine oxidation as compared with native-and total LDL. LC/MS/MS analyses of LDL − revealed specific modifications in the apoB-100 moiety, largely involving nitration of tyrosines in the α-helical structures and β 2 sheet as well as cysteine oxidation to cysteic acid in β 1 sheet. Circular dichroism analyses showed that the α-helical content of LDL − was substantially lower (~25%) than that of native LDL (~90%); conversely, LDL − showed greater content of β-sheet and random coil structure, in agreement with unfolding of the protein. These results were mimicked by treatment of LDL subfractions with peroxynitrite (ONOO − ) or SIN-1: similar amino acid modifications as well as conformational changes (loss of α-helical structure and gain in β-sheet structure) were observed. Both LDL − and ONOO − -treated LDL showed a statistically significant increase in binding and uptake to-and by BAEC compared to native LDL. We further found that most binding and uptake in control-LDL was through LDL-R with minimal oxLDL-R-dependent uptake. ONOO − -treated LDL was significantly bound and endocytosed by LOX-1, CD36 and SR-A with minimal contribution from LDL-R. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. It is suggested that lipid peroxidation and protein nitration may account for the mechanisms leading to apoB-100 protein unfolding and consequential increase in modified LDL binding and uptake to and by endothelial cells that is dependent on oxLDL scavenger receptors. NIH Public Access

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Effect of Chronic Treatment With the Inducible Nitric Oxide Synthase Inhibitor N -Iminoethyl- l -Lysine or With l -Arginine on Progression of Coronary and Aortic Atherosclerosis in Hypercholesterolemic Rabbits

Abstract: This is the first study showing that chronic treatment with an iNOS inhibitor, L-NIL, limits progression of preexisting atherosclerosis in hypercholesterolemic rabbits. Increased intimal collagen accumulation may participate in iNOS-induced atherosclerosis progression.

Cited by 72 publications

References 41 publications

Effect of early versus late AT₁ receptor blockade with losartan on postmyocardial infarction ventricular remodeling in rabbits

Effect of early versus late AT₁ receptor blockade with losartan on postmyocardial infarction ventricular remodeling in rabbits

Atorvastatin Increases Endoglin, SMAD2, Phosphorylated SMAD2/3 and eNOS Expression in ApoE/LDLR Double Knockout Mice

LDL protein nitration: Implication for LDL protein unfolding

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