NO/NOS‐Dependent Modulation of Inflammation in Acrolein‐Induced Vascular Toxicity

Abstract

Modulation of inflammatory signaling has been elucidated in different disease models including vascular biology. No/NOS system plays an important role in the process of inflammation. Balance between nitric oxide (NO) and superoxide is critical in inflammatory process. Peroxisome proliferator‐activated receptor gamma (PPARγ) has been implicated in pathology of diseases involving inflammation and in our previous studies we reported reduction in PPARγ protein expression and activity in animals exposed to acrolein. Since PPARγ influences both NO and superoxide generation, in this study we are proposing involvement of impairment of this regulation in acrolein‐mediated inflammatory response. Male iNOS knockout (inducible nitric oxide synthase, KO) mice were treated with acrolein (0.5 μg/kg; i.p.; 7 days) with/without rosiglitazone (Roz: PPARγ ligand, 10 mg/kg; orally; 10 days). Age/weight matched wild type (WT) were used as control. Urine and kidney tissue was processed for western blot and biochemical analysis. KO mice had higher (87%) 8‐Isoprostane in response to acrolein but lower NO (23%) compared to WT. Roz reduced 8‐isoprostane in KO mice by 47% and increased NO production by 35%. Total Antioxidant Status (TAS) was reduced in WT (31%) and KO (53%) mice treated with acrolein. Roz improved TAS in both KO (33%) and WT (21%) mice. Acrolein did not affect expression of eNOS (endothelial nitric oxide synthase) in WT and KO mice. Roz increased eNOS expression in WT (23%) and KO (33%) and iNOS expression in WT (28%). Expression of PPARγ was increased in WT (30%) and KO (28%) mice treated with acrolein and was further increased with addition of Roz (89% & 102% respectively). Based on these data, we are concluding that acrolein‐mediated reduction in PPARγ affects eNOS/iNOS/NO pathway and activation of PPARγ minimizes acrolein effect by improving PPARγ‐dependent NO/NOS interaction.Support or Funding InformationNIH, SC3GM103746This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.