The phosphodiesterase 5 inhibitor sildenafil decreases the proinflammatory chemokine IL-8 in diabetic cardiomyopathy: in vivo and in vitro evidence

摘要

PurposeInterleukin (IL)-8 is a proinflammatory C-X-C chemokine involved in inflammation underling cardiac diseases, primary or in comorbid condition, such diabetic cardiomyopathy (DCM). The phosphodiesterase type 5 inhibitor sildenafil can ameliorate cardiac conditions by counteracting inflammation. The study aim is to evaluate the effect of sildenafil on serum IL-8 in DCM subjects vs. placebo, and on IL-8 release in human endothelial cells (Hfaec) and peripheral blood mononuclear cells (PBMC) under inflammatory stimuli.MethodsIL-8 was quantified: in sera of (30) DCM subjects before (baseline) and after sildenafil (100mg/day, 3-months) vs. (16) placebo and (15) healthy subjects, by multiplatform array; in supernatants from inflammation-challenged cells after sildenafil (1 mu M), by ELISA.ResultsBaseline IL-8 was higher in DCM vs. healthy subjects (149.1446.89 vs. 16.17 +/- 5.38pg/ml, p<0.01). Sildenafil, not placebo, significantly reduced serum IL-8 (23.7 +/- 5.9pg/ml, p<0.05 vs. baseline). Receiver operating characteristic (ROC) curve for IL-8 was 0.945 (95 confidence intervalof 0.772 to 1.0, p<0.01), showing good capacity of discriminating the response in terms of drug-induced IL-8 decrease (sensitivity of 0.93, specificity of 0.90). Sildenafil significantly decreased IL-8 protein release by inflammation-induced Hfaec and PBMC and downregulated IL-8 mRNA in PBMC, without affecting cell number or PDE5 expression.ConclusionSildenafil might be suggested as potential novel pharmacological tool to control DCM progression through IL-8 targeting at systemic and cellular level.