title: Cardiac inflammation after local irradiation is influenced by the kallikrein-kinin system.
abstract: Radiotherapy of intrathoracic and chest wall tumors may lead to exposure of the heart to ionizing radiation, resulting in radiation-induced heart diseases (RIHD). The main manifestations of RIHD become apparent many years after treatment and include cardiomyopathy and accelerated atherosclerosis. This study examines the role of the kallikrein-kinin system (KKS) in RIHD by investigating the cardiac radiation response in a kininogen-deficient Brown Norway Katholiek (BN/Ka) rat model. BN/Ka rats and wild-type Brown Norway (BN) rats were exposed to local heart irradiation with a single dose of 18 Gy or 24 Gy and were observed for 3 to 6 months. Examinations included in vivo and ex vivo cardiac function, histopathology, gene and protein expression measurements, and mitochondrial swelling assays. Upon local heart irradiation, changes in in vivo cardiac function were significantly less in BN/Ka rats. For instance, a single dose of 24 Gy caused a 35% increase in fractional shortening in BN rats compared with a 16% increase in BN/Ka rats. BN rats, but not BN/Ka rats, showed a 56% reduction in cardiac numbers of CD2-positive cells, and a 57% increase in CD68-positive cells, together with a 52% increase in phosphorylation of extracellular signal-regulated kinase 1/2 (Erk1/2). Local heart irradiation had similar effects on histopathology, mitochondrial changes, and left ventricular mRNA levels of NADPH oxidases in the two genotypes. These results suggest that the KKS plays a role in the effects of radiation on cardiac function and recruitment of inflammatory cells. The KKS may have these effects at least in part by altering Erk1/2 signaling.
authors.affiliation: Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
authors.forename: Vijayalakshmi
authors.initials: V
authors.lastname: Sridharan
authors.forename: Preeti
authors.initials: P
authors.lastname: Tripathi
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Sharma
authors.forename: Eduardo G
authors.initials: EG
authors.lastname: Moros
authors.forename: Peter M
authors.initials: PM
authors.lastname: Corry
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Lieblong
authors.forename: Elena
authors.initials: E
authors.lastname: Kaschina
authors.forename: Thomas
authors.initials: T
authors.lastname: Unger
authors.forename: Christa
authors.initials: C
authors.lastname: Thöne-Reineke
authors.forename: Martin
authors.initials: M
authors.lastname: Hauer-Jensen
authors.forename: Marjan
authors.initials: M
authors.lastname: Boerma
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D015153:Blotting, Western; D018801:CD2 Antigens / Q000032:analysis; D015870:Gene Expression / Q000528:radiation effects; D006321:Heart / Q000503:physiopathology* / Q000528:radiation effects; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D016234:Kallikrein-Kinin System; D007704:Kininogens / Q000172:deficiency* / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000528:radiation effects; D008933:Mitochondrial Swelling / Q000528:radiation effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009205:Myocarditis / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D019255:NADPH Oxidases / Q000235:genetics; D010766:Phosphorylation / Q000528:radiation effects; D011833:Radiation Injuries, Experimental / Q000150:complications; D051381:Rats; D011914:Rats, Inbred BN; D043782:Receptor, Bradykinin B2 / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D018801:CD2 Antigens; D007704:Kininogens; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019255:NADPH Oxidases; D043782:Receptor, Bradykinin B2; C067980:CD68 antigen, human; D000097382:CD68 Molecule