Bongartz LG, Braam B, Verhaar MC, Cramer MJ, Goldschmeding R, Gaillard CA, Steendijk P, Doevendans PA, Joles JA. The nitric oxide donor molsidomine rescues cardiac function in rats with chronic... Show moreBongartz LG, Braam B, Verhaar MC, Cramer MJ, Goldschmeding R, Gaillard CA, Steendijk P, Doevendans PA, Joles JA. The nitric oxide donor molsidomine rescues cardiac function in rats with chronic kidney disease and cardiac dysfunction. Am J Physiol Heart Circ Physiol 299: H2037-H2045, 2010. First published September 17, 2010; doi: 10.1152/ajpheart.00400.2010.-We recently developed a rat model of cardiorenal failure that is characterized by severe left ventricular systolic dysfunction (LVSD) and low nitric oxide (NO) production that persisted after temporary low-dose NO synthase inhibition. We hypothesized that LVSD was due to continued low NO availability and might be reversed by supplementing NO. Rats underwent a subtotal nephrectomy and were treated with low-dose NO synthase inhibition with N-omega-nitro-L-arginine up to week 8. After 3 wk of washout, rats were treated orally with either the long-acting, tolerance-free NO donor molsidomine (Mols) or vehicle (Veh). Cardiac and renal function were measured on weeks 11, 13, and 15. On week 16, LV hemodynamics and pressure-volume relationships were measured invasively, and rats were killed to quantify histological damage. On week 15, blood pressure was mildly reduced and creatinine clearance was increased by Mols (both P < 0.05). Mols treatment improved ejection fraction (53 +/- 3% vs. 37 +/- 2% in Veh-treated rats, P < 0.001) and stroke volume (324 +/- 33 vs. 255 +/- 15 mu 1 in Veh-treated rats, P < 0.05). Rats with Mols treatment had lower end-diastolic pressures (8.5 +/- 1.1 mmHg) than Veh-treated rats (16.3 +/- 3.5 mmHg, P < 0.05) and reduced time constants of relaxation (21.9 +/- 1.8 vs. 30.9 +/- 3.3 ms, respectively, P < 0.05). The LV end-systolic pressure-volume relationship was shifted to the left in Mols compared with Veh treatment. In summary, in a model of cardiorenal failure with low NO availability, supplementing NO significantly improves cardiac systolic and diastolic function without a major effect on afterload. Show less
Bluyssen HA, Rastmanesh MM, Tilburgs C, Jie K, Wesseling S, Goumans M, Boer P, Joles JA, Braam B. IFN gamma-dependent SOCS3 expression inhibits IL-6-induced STAT3 phosphorylation and differentially... Show moreBluyssen HA, Rastmanesh MM, Tilburgs C, Jie K, Wesseling S, Goumans M, Boer P, Joles JA, Braam B. IFN gamma-dependent SOCS3 expression inhibits IL-6-induced STAT3 phosphorylation and differentially affects IL-6 mediated transcriptional responses in endothelial cells. Am J Physiol Cell Physiol 299: C354-C362, 2010. First published May 19, 2010; doi: 10.1152/ajpcell.00513.2009.-IL-6 has pro- and anti-inflammatory effects and is involved in endothelial cell (EC) dysfunction. The anti-inflammatory effects of IL-6 are mediated by signal transducer and activator of transcription-3 (STAT3), which is importantly controlled by suppressor of cytokine signaling 3 (SOCS3). Therefore, cytokines that modulate SOCS3 expression might inhibit the anti-inflammatory effects of IL-6. We hypothesized that in EC, interferon-gamma (IFN gamma)-induced SOCS3 expression leads to inhibition of IL-6-induced STAT3 activation and IL-6-dependent expression of anti-, but not pro-inflammatory, target genes. IFN gamma activated STAT1 and STAT3 and increased SOCS3 expression in EC. IL-6 only activated STAT3 and induced SOCS3 expression. IFN gamma pretreatment of EC inhibited IL-6-induced STAT3 activation accompanied by increased SOCS3 protein. Inhibition of SOCS3 expression, using costimulation, Act-D, and small interfering RNA (siRNA), subsequently implicated the importance of IFN gamma-induced SOCS3 in this phenomenon. Pretreatment of EC with IFN gamma also affected the transcriptional program induced by IL-6. We identified 1) IL-6 anti-inflammatory target genes that were inhibited by IFN gamma, 2) IFN gamma-target genes of pro-inflammatory nature that were increased in response to IL-6 in the presence of IFN gamma, and 3) a set of target genes that were increased upon IL-6 or IFN gamma alone, or combined IFN gamma and IL-6. In summary, by increasing SOCS3 expression in EC, IFN gamma can selectively inhibit STAT3-dependent IL-6 signaling. This in turn leads to decreased expression of some EC protective genes. In contrast, other genes of pro-inflammatory nature are not inhibited or even increased. This IFN gamma-induced shift in IL-6 signaling to a pro-inflammatory phenotype could represent a novel mechanism involved in EC dysfunction. Show less
