title: Interleukin-1beta enhanced action of kinins on extracellular matrix of spontaneous hypertensive rat cardiac fibroblasts.
abstract: Interaction between an enhanced action of kinins and cytokines is accepted as important to the cardioprotective effect of angiotensin-converting-enzyme inhibitors. Kinins mediate their effects through B1 and B2 subtype receptors that may be modulated by cytokines including interleukin (IL)-1beta. We examined expression of kinin receptors and the effects of bradykinin (B2 agonist) and des-Arg10-kallidin (B1 agonist) on extracellular matrix components of adult rat cardiac fibroblasts with or without prior exposure to IL-1beta. We compared responses of cells cultured from spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) hearts. mRNA levels of kinin receptors, procollagens, promatrix metalloproteinases (proMMP-2 and proMMP-9), and tissue inhibitors of metalloproteinase (TIMP-1 and TIMP-2) were all assessed by a semiquantitative RT-PCR. In the absence of IL-1beta, SHR cells expressed more B2 receptor, procollagen alpha1(I), procollagen alpha1(III), and proMMP-9 mRNA than WKY cells. IL-1beta exposure enhanced B1, B2, proMMP-2, and proMMP-9 mRNA in cells of both strains to equivalent levels. Zymographic studies confirmed the results of proMMPs. Following IL-1beta treatment, bradykinin attenuated procollagens alpha1(I) and alpha1(III) mRNA expression in SHR but not WKY cells. In contrast, des-Arg10-kallidin did not show any significant effects in either SHR or WKY cells. Our findings indicate greater extracellular matrix turnover in cultured SHR cardiac fibroblasts than WKY under basal conditions, an IL-1beta stimulation of turnover in cells from both strains, and a strain-differential effect of bradykinin following cytokine treatment. These results imply a genetically determined response of cardiac extracellular matrix and the potential of direct enhancement of the efficacy of kinins by the local release of IL-1beta in hearts genetically programmed to exhibit excessive remodeling to injury.
authors.affiliation: Department of Pharmacology, School of Medicine, University of California at San Diego, La Jolla, California 92093, USA. JBH00576@nifty.ne.jp
authors.forename: Chiharu
authors.initials: C
authors.lastname: Imai
authors.forename: Atsunori
authors.initials: A
authors.lastname: Okamura
authors.forename: Jian Feng
authors.initials: JF
authors.lastname: Peng
authors.forename: Yudai
authors.initials: Y
authors.lastname: Kitamura
authors.forename: Morton P
authors.initials: MP
authors.lastname: Printz
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000494:pharmacology*; D002478:Cells, Cultured; D017364:Collagenases / Q000235:genetics; D004357:Drug Synergism; D004792:Enzyme Precursors / Q000235:genetics; D005109:Extracellular Matrix / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D018093:Gelatinases / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology*; D007375:Interleukin-1 / Q000494:pharmacology*; D007609:Kallidin / Q000031:analogs & derivatives* / Q000494:pharmacology; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000235:genetics; D009206:Myocardium / Q000166:cytology*; D011347:Procollagen / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D043783:Receptor, Bradykinin B1 / Q000235:genetics; D043782:Receptor, Bradykinin B2 / Q000235:genetics; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics
chemical_list: D004792:Enzyme Precursors; D007375:Interleukin-1; D011347:Procollagen; D012333:RNA, Messenger; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D007609:Kallidin; C052787:kallidin, des-Arg(10)-; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; C120487:pro-matrix metalloproteinase 9; C069860:progelatinase; D020780:Matrix Metalloproteinase 9; D001920:Bradykinin