Cytokines decrease sGC in pulmonary artery smooth muscle cells via NO-dependent and NO-independent mechanisms

Exposure of rat pulmonary artery smooth muscle cells (rPASMC) to cytokines leads to nitric oxide (NO) production by NO synthase 2 (NOS2). NO stimulate s cGMP synthesis by soluble guanylate cyclase (sGC), a heterodimer composed of alpha (1)- and beta (1)-subunits. Prolonged exposure of rPASMC to NO de creases sGC subunit mRNA and protein levels. The objective of this study wa s to determine whether levels of NO produced endogenously by NOS2 are suffi cient to decrease sGC expression in rPASMC. Interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) increased NOS2 mRNA levels and decreased sGC subunit mRNA levels. Exposure of rPASMC to IL-1 beta and TNF- alpha for 24 h decreased sGC subunit protein levels and NO-stimulated sGC e nzyme activity. L-N-6-(1-iminoethyl) lysine (NOS2 inhibitor) or 1H-[1,2,4]o xadiazolo-[4,3-a]quinoxalin-1-one (sGC inhibitor) partially prevented the c ytokine-mediated decrease in sGC subunit mRNA levels. However, cytokines al so decreased sGC subunit mRNA levels in PASMC derived from NOS2-deficient m ice. These results demonstrate that levels of NO and cGMP produced in cytok ine-exposed PASMC are sufficient to decrease sGC subunit mRNA levels. In ad dition, cytokines can decrease sGC subunit mRNA levels via NO-independent m echanisms.