Lipopolysaccharides and cytokines downregulate the angiotensin II type 2 receptor in rat cardiac fibroblasts

The present study examines the effect of lipopolysaccharides and proinflamm atory cytokines on the expression of the second isoform of the angiotensin II receptor (AT(2)), which may have a role in lowering collagen deposition in cardiac tissue. Cardiac fibroblasts express high levels of both angioten sin II type 1 (AT(1)) and type 2 receptors. Incubation with lipopolysacchar ides for 24 h dose- and time-dependently decreased angiotensin II AT(2) rec eptor expression with no apparent difference in the affinity. Actinomycin D , cycloheximide, N-omega-nitro-L-arginine methyl ester and the protein tyro sine kinase inhibitor herbimycin A, but not the protein kinase C inhibitors bisindolylmaleimide and calphostin C, abolished the inhibitory action of l ipopolysaccharides. The cytokines interleukin-1 beta and tissue necrosis fa ctor-alpha mimicked the effect of lipopolysaccharides. All three compounds induced inducible nitric oxide synthase (iNOS). The nitric oxide donor sodi um nitroprusside and the cGMP analog 8-bromoguanosine cyclic monophosphate downregulated angiotensin II AT(2) receptor expression. The findings are co nsistent with the pathway in which lipopolysaccharides or cytokines induce iNOS. The data suggest that lipopolysaccharide- or cytolkine-dependent indu ction of iNOS and resultant production of nitric oxide leads to the product ion of cGMP, which in turn downregulates expression of the angiotensin Il A T(2) receptor in cardiac fibroblasts. (C) 1999 Elsevier Science B.V. All ri ghts reserved.