title: Cardiac angiotensin II participates in coronary microvessel inflammation of unstable angina and strengthens the immunomediated component.
abstract: Angiotensin (Ang) II is now recognized to be a mediator of a wide variety of inflammatory processes. This study investigated renin-angiotensin system (RAS) components and a number of inflammatory mediators in left ventricular biopsies from 2-vessel disease unstable angina (UA) (n=43) and stable angina (SA) (n=15) patients undergoing coronary bypass surgery. Biopsy samples from 6 patients undergoing valve replacement for mitral stenosis served as controls. UA patients were randomly assigned to angiotensin-converting enzyme (ACE)-inhibitor (ramipril), AT1 antagonist (valsartan), or placebo and treated during the 5 days preceding coronary bypass surgery, performed from 6 to 9 days after coronary angiography. During coronary angiography coronary blood flow was measured and samples were obtained from aorta and coronary sinus for determination of Ang I and Ang II gradients. The hearts of UA patients produced Ang II in a greater amount than in SA patients (P<0.01). UA biopsy samples showed numerous DR+ cells, identified as lymphocytes, macrophages, and endothelial cells. Reverse-transcriptase polymerase chain reaction showed overexpression of AGTN, ACE, and AT1-R genes, as well as upregulation of TNF-alpha, IL-6, IFN-gamma, and iNOS genes (P<0.01), with no differences between nonischemic and potentially ischemic areas. AGTN, ACE, and cytokine genes were mainly localized on endothelial cells. Ramipril and valsartan markedly decreased the expression levels of TNF-alpha, IL-6, and iNOS, and, to a lesser extent, of IFN-gamma genes, but did not affect the number of DR+ cells, with no significant difference between the 2 treatments. These results show that locally generated Ang II amplifies the immunomediated inflammatory process of coronary microvessels occurring in unstable angina.
authors.affiliation: Clinica Medica Generale e Cardiologia, University of Florence, Viale Morgagni 85, 50134 Florence, Italy. gg.neriserneri@dfc.unifi.it
authors.forename: Gian Gastone
authors.initials: GG
authors.lastname: Neri Serneri
authors.forename: Maria
authors.initials: M
authors.lastname: Boddi
authors.forename: Pietro Amedeo
authors.initials: PA
authors.lastname: Modesti
authors.forename: Mirella
authors.initials: M
authors.lastname: Coppo
authors.forename: Ilaria
authors.initials: I
authors.lastname: Cecioni
authors.forename: Thomas
authors.initials: T
authors.lastname: Toscano
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Papa
authors.forename: Manuela
authors.initials: M
authors.lastname: Bandinelli
authors.forename: Gian Franco
authors.initials: GF
authors.lastname: Lisi
authors.forename: Mario
authors.initials: M
authors.lastname: Chiavarelli
mesh_terms: D000328:Adult; D000368:Aged; D000787:Angina Pectoris / Q000150:complications / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology / Q000601:surgery; D000789:Angina, Unstable / Q000150:complications / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology* / Q000601:surgery; D000804:Angiotensin II / Q000096:biosynthesis / Q000502:physiology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D053818:Chymases; D003131:Combined Modality Therapy; D017023:Coronary Angiography; D001026:Coronary Artery Bypass; D003326:Coronary Circulation; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D008875:Middle Aged; D008946:Mitral Valve Stenosis / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D011300:Preoperative Care; D012333:RNA, Messenger / Q000096:biosynthesis; D017257:Ramipril / Q000494:pharmacology / Q000627:therapeutic use; D012084:Renin-Angiotensin System / Q000235:genetics / Q000502:physiology; D012697:Serine Endopeptidases / Q000096:biosynthesis / Q000235:genetics; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000068756:Valsartan; D014657:Vasculitis / Q000188:drug therapy / Q000209:etiology / Q000276:immunology / Q000503:physiopathology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D016207:Cytokines; D012333:RNA, Messenger; D013777:Tetrazoles; D000804:Angiotensin II; D000068756:Valsartan; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D012697:Serine Endopeptidases; D053818:Chymases; D014633:Valine; D017257:Ramipril