Treatment with Angiotensin-(1–7) reduces inflammation in carotid atherosclerotic plaques

Rodrigo A. Fraga-Silva; Silvia Q. Savergnini; Fabrizio Montecucco; Alessio Nencioni; Irene Caffa; Debora Soncini; Fabiana P. Costa-Fraga; Frederico B. De Sousa; Ruben D. Sinisterra; Luciano A. S. Capettini; Sébastien Lenglet; Katia Galan; Graziano Pelli; Maria Bertolotto; Aldo Pende; Giovanni Spinella; Bianca Pane; Franco Dallegri; Domenico Palombo; François Mach; Nikolaos Stergiopulos; Robson A. S. Santos; Rafaela F. da Silva

doi:10.1160/TH13-06-0448

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2014; 111(04): 736-747
DOI: 10.1160/TH13-06-0448

Cardiovascular Biology and Cell Signalling

Schattauer GmbH

Treatment with Angiotensin-(1–7) reduces inflammation in carotid atherosclerotic plaques

Rodrigo A. Fraga-Silva

¹Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

,

Silvia Q. Savergnini

¹Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

,

Fabrizio Montecucco

²Division of Cardiology, Faculty of Medicine, Foundation for Medical Researches, University of Geneva, Geneva, Switzerland

³First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino–IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

,

Alessio Nencioni

³First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino–IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

,

Irene Caffa

³First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino–IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

,

Debora Soncini

³First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino–IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

,

Fabiana P. Costa-Fraga

¹Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

,

Frederico B. De Sousa

⁴Department of Chemistry, Federal University of Minas Gerais, Brazil

,

Ruben D. Sinisterra

⁴Department of Chemistry, Federal University of Minas Gerais, Brazil

,

Luciano A. S. Capettini

¹Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

,

Sébastien Lenglet

²Division of Cardiology, Faculty of Medicine, Foundation for Medical Researches, University of Geneva, Geneva, Switzerland

,

Katia Galan

²Division of Cardiology, Faculty of Medicine, Foundation for Medical Researches, University of Geneva, Geneva, Switzerland

,

Graziano Pelli

²Division of Cardiology, Faculty of Medicine, Foundation for Medical Researches, University of Geneva, Geneva, Switzerland

,

Maria Bertolotto

³First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino–IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

,

Aldo Pende

³First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino–IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

,

Giovanni Spinella

⁵Vascular and Endovascular Surgery Unit, Department of Surgery, San Martino Hospital, Genoa, Italy

,

Bianca Pane

⁵Vascular and Endovascular Surgery Unit, Department of Surgery, San Martino Hospital, Genoa, Italy

,

Franco Dallegri

³First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino–IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

,

Domenico Palombo

⁵Vascular and Endovascular Surgery Unit, Department of Surgery, San Martino Hospital, Genoa, Italy

,

François Mach

²Division of Cardiology, Faculty of Medicine, Foundation for Medical Researches, University of Geneva, Geneva, Switzerland

,

Nikolaos Stergiopulos

¹Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

,

Robson A. S. Santos^#

⁶Department of Physiology and Biophysics, Federal University of Minas Gerais, Brazil

,

Rafaela F. da Silva^#

⁶Department of Physiology and Biophysics, Federal University of Minas Gerais, Brazil

› Author Affiliations

Abstract

Summary

Angiotensin (Ang)-(1–7), acting through the receptor Mas, has atheroprotective effects; however, its role on plaque vulnerability has been poorly studied. Here, we investigated the expression of the renin-angiotensin system (RAS) components in stable and unstable human carotid plaques. In addition, we evaluated the effects of the chronic treatment with an oral formulation of Ang-(1–7) in a mouse model of shear stress-determined carotid atherosclerotic plaque. Upstream and downstream regions of internal carotid plaques were obtained from a recently published cohort of patients asymptomatic or symptomatic for ischaemic stroke. Angiotensinogen and renin genes were strongly expressed in the entire cohort, indicating an intense intraplaque modulation of the RAS. Intraplaque expression of the Mas receptor mRNA was increased in the downstream portion of asymptomatic patients as compared to corresponding region in symptomatic patients. Conversely, AT1 receptor gene expression was not modified between asymptomatic and symptomatic patients. Treatment with Ang-(1–7) in ApoE^-/- mice was associated with increased intraplaque collagen content in the aortic root and low shear stress-induced carotid plaques, and a decreased MMP-9 content and neutrophil and macrophage infiltration. These beneficial effects were not observed in the oscillatory shear stress-induced plaque. In vitro incubation with Ang-(1–7) did not affect ICAM-1 expression and apoptosis on cultured endothelial cells. In conclusion, Mas receptor is up regulated in the downstream portions of human stable carotid plaques as compared to unstable lesions. Treatment with the oral formulation of Ang-(1–7) enhances a more stable phenotype in atherosclerotic plaques, depending on the local pattern of shear stress forces.

Keywords

Angiotensin - atherosclerosis - inflammation - plaque stability

Full Text

References

References
1 Yusuf S, Reddy S, Ounpuu S. et al. Global burden of cardiovascular diseases: Part i: General considerations, the epidemiologic transition, risk factors, and impact of urbanization.. Circulation 2001; 104: 2746-2753.
2 Kolodgie FD, Gold HK, Burke AP. et al. Intraplaque hemorrhage and progression of coronary atheroma.. N Engl J Med 2003; 349: 2316-2325.
3 Waxman S, Ishibashi F, Muller JE. Detection and treatment of vulnerable plaques and vulnerable patients: Novel approaches to prevention of coronary events.. Circulation 2006; 114: 2390-2311.
4 Cheng C, Tempel D, van Haperen R. et al. Atherosclerotic lesion size and vulnerability are determined by patterns of fluid shear stress.. Circulation 2006; 113: 2744-2753.
5 Chatzizisis YS, Jonas M, Coskun AU. et al. Prediction of the localization of high-risk coronary atherosclerotic plaques on the basis of low endothelial shear stress: An intravascular ultrasound and histopathology natural history study.. Circulation 2008; 117: 993-1002.
6 Koskinas KC, Chatzizisis YS, Baker AB. et al. The role of low endothelial shear stress in the conversion of atherosclerotic lesions from stable to unstable plaque.. Curr Opin Cardiol 2009; 24: 580-590.
7 Weiss D, Kools JJ, Taylor WR. Angiotensin ii-induced hypertension accelerates the development of atherosclerosis in apoe-deficient mice.. Circulation 2001; 103: 448-454.
8 Mazzolai L, Duchosal MA, Korber M. et al. Endogenous angiotensin II induces atherosclerotic plaque vulnerability and elicits a th1 response in apoe-/- mice.. Hypertension 2004; 44: 277-282.
9 Keidar S, Attias J, Heinrich R. et al. Angiotensin ii atherogenicity in apolipoprotein e deficient mice is associated with increased cellular cholesterol biosynthesis.. Atherosclerosis 1999; 146: 249-257.
10 Ni W, Kitamoto S, Ishibashi M. et al. Monocyte chemoattractant protein-1 is an essential inflammatory mediator in angiotensin ii-induced progression of established atherosclerosis in hypercholesterolemic mice.. Arterioscler Thromb Vasc Biol 2004; 24: 534-539.
11 Victorino GP, Newton CR, Curran B. Effect of angiotensin ii on microvascular permeability.. J Surg Res 2002; 104: 77-81.
12 Keidar S, Heinrich R, Kaplan M. et al. Angiotensin ii administration to atherosclerotic mice increases macrophage uptake of oxidized ldl: A possible role for interleukin-6.. Arterioscler Thromb Vasc Biol 2001; 21: 1464-1469.
13 Osada-Oka M, Kita H, Yagi S. et al. Angiotensin at1 receptor blockers suppress oxidized low-density lipoprotein-derived formation of foam cells.. Eur J Pharmacol 2012; 679: 9-15.
14 Nickenig G, Harrison DG. The AT(1)-type angiotensin receptor in oxidative stress and atherogenesis: Part ii: AT(1) receptor regulation.. Circulation 2002; 105: 530-536.
15 Hernandez-Presa M, Bustos C, Ortego M. et al. Angiotensin-converting enzyme inhibition prevents arterial nuclear factor-kappa b activation, monocyte chemoattractant protein-1 expression, and macrophage infiltration in a rabbit model of early accelerated atherosclerosis.. Circulation 1997; 95: 1532-1541.
16 Tham DM, Martin-McNulty B, Wang YX. et al. Angiotensin ii is associated with activation of nf-kappab-mediated genes and downregulation of ppars.. Physiol Genomics 2002; 11: 21-30.
17 Ishibashi M, Hiasa K, Zhao Q. et al. Critical role of monocyte chemoattractant protein-1 receptor ccr2 on monocytes in hypertension-induced vascular inflammation and remodeling.. Circ Res 2004; 94: 1203-1210.
18 Bader M. Tissue renin-angiotensin-aldosterone systems: Targets for pharmacological therapy.. Annu Rev Pharmacol Toxicol 2010; 50: 439-465.
19 Ferreira AJ, Murca TM, Fraga-Silva RA. et al. New cardiovascular and pulmonary therapeutic strategies based on the angiotensin-converting enzyme 2/angio-tensin-(1-7)/mas receptor axis.. Int J Hypertens 2012; 2012: 147825.
20 Ferreira AJ, Santos RA. Cardiovascular actions of angiotensin-(1-7).. Braz J Med Biol Res 2005; 38: 499-507.
21 Ferreira AJ, Santos RA, Bradford CN. et al. Therapeutic implications of the va-soprotective axis of the renin-angiotensin system in cardiovascular diseases.. Hypertension 2010; 55: 207-213.
22 Santos RA, Simoes e Silva AC, Maric C. et al. Angiotensin-(1-7) is an endogenous ligand for the g protein-coupled receptor mas.. Proc Natl Acad Sci USA 2003; 100: 8258-8263.
23 Tesanovic S, Vinh A, Gaspari TA. et al. Vasoprotective and atheroprotective effects of angiotensin (1-7) in apolipoprotein e-deficient mice.. Arterioscler Thromb Vasc Biol 2010; 30: 1606-1613.
24 Jawien J, Toton-Zuranska J, Gajda M. et al. Angiotensin-(1-7) receptor mas agonist ameliorates progress of atherosclerosis in apoe-knockout mice.. J Physiol Pharmacol 2012; 63: 77-85.
25 Wang Y, Tikellis C, Thomas MC, Golledge J. Angiotensin converting enzyme 2 and atherosclerosis.. Atherosclerosis 2013; 226: 3-8.
26 Lula I, Denadai AL, Resende JM. et al. Study of angiotensin-(1-7) vasoactive peptide and its beta-cyclodextrin inclusion complexes: Complete sequence-specific nmr assignments and structural studies.. Peptides 2007; 28: 2199-2210.
27 Fraga-Silva RA, Costa-Fraga FP, De Sousa FB. et al. An orally active formulation of angiotensin-(1-7) produces an antithrombotic effect.. Clinics 2011; 66: 837-841.
28 Montecucco F, Lenglet S, Gayet-Ageron A. et al. Systemic and intraplaque mediators of inflammation are increased in patients symptomatic for ischaemic stroke.. Stroke 2010; 41: 1394-1404.
29 Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST).. Lancet 1998; 351: 1379-1387.
30 Barnett HJ, Taylor DW, Eliasziw M. et al. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. North american symptomatic carotid endarterectomy trial collaborators.. N Engl J Med 1998; 339: 1415-1425.
31 Halliday A, Mansfield A, Marro J. et al. Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: Randomised controlled trial.. Lancet 2004; 363: 1491-1502.
32 Montecucco F, Di Marzo V, da Silva RF. et al. The activation of the cannabinoid receptor type 2 reduces neutrophilic protease-mediated vulnerability in atherosclerotic plaques.. Eur Heart J 2012; 33: 846-856.
33 Olivon VC, Fraga-Silva RA, Segers D. et al. Arginase inhibition prevents the low shear stress-induced development of vulnerable atherosclerotic plaques in apoe-/- mice.. Atherosclerosis 2013; 227: 236-243.
34 Montecucco F, Vuilleumier N, Pagano S. et al. Anti-apolipoprotein a-1 auto-antibodies are active mediators of atherosclerotic plaque vulnerability.. Eur Heart J 2011; 32: 412-421.
35 Feltenberger JD, Andrade JM, Paraiso A. et al. Oral formulation of angioten-sin-(1-7) improves lipid metabolism and prevents high-fat diet-induced hepatic steatosis and inflammation in mice.. Hypertension 2013; 62: 324-330.
36 Marques FD, Ferreira AJ, Sinisterra RD. et al. An oral formulation of angioten-sin-(1-7) produces cardioprotective effects in infarcted and isoproterenol-treated rats.. Hypertension 2011; 57: 477-483.
37 Ramkhelawon B, Vilar J, Rivas D. et al. Shear stress regulates angiotensin type 1 receptor expression in endothelial cells.. Circ Res 2009; 105: 869-875.
38 Vickers C, Hales P, Kaushik V. et al. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase.. J Biol Chem 2002; 277: 14838-14843.
39 Zisman LS, Meixell GE, Bristow MR, Canver CC. Angiotensin-(1-7) formation in the intact human heart: In vivo dependence on angiotensin ii as substrate.. Circulation 2003; 108: 1679-1681.
40 Campbell DJ, Zeitz CJ, Esler MD. et al. Evidence against a major role for angio-tensin converting enzyme-related carboxypeptidase (ace2) in angiotensin pep-tide metabolism in the human coronary circulation.. J Hypertens 2004; 22: 1971-1976.
41 Sluimer JC, Gasc JM, Hamming I. et al. Angiotensin-converting enzyme 2 (ace2) expression and activity in human carotid atherosclerotic lesions.. J Pathol 2008; 215: 273-279.
42 Fraga-Silva RA, Ferreira AJ, Dos Santos RA. Opportunities for targeting the an-giotensin-converting enzyme 2/angiotensin-(1-7)/mas receptor pathway in hypertension.. Curr Hypertens Rep 2013; 15: 31-38.
43 Caro CG, Fitz-Gerald JM, Schroter RC. Arterial wall shear and distribution of early atheroma in man.. Nature 1969; 223: 1159-1160.
44 Dai G, Kaazempur-Mofrad MR, Natarajan S. et al. Distinct endothelial pheno-types evoked by arterial waveforms derived from atherosclerosis-susceptible and -resistant regions of human vasculature.. Proc Natl Acad Sci USA 2004; 101: 14871-14876.
45 Dong B, Zhang C, Feng JB. et al. Overexpression of ace2 enhances plaque stability in a rabbit model of atherosclerosis.. Arterioscler Thromb Vasc Biol 2008; 28: 1270-1276.
46 Yamada K, Iyer SN, Chappell MC, Ganten D, Ferrario CM. Converting enzyme determines plasma clearance of angiotensin-(1-7).. Hypertension 1998; 32: 496-502.
47 Uekama K. Design and evaluation of cyclodextrin-based drug formulation.. Chem Pharm Bull 2004; 52: 900-915.
48 World Intellectual Property Organization. Process of preparation of formulations of the peptide angiotensin-(1-7) and its analogues, agonistic and antagonists using cyclodextrins, lipossomes and biodegradable polymers and/or mixtures and products thereof. Available at: http://patentscope.wipo.int/search/en/WO2003039434 . Accessed October 18, 2013.