Nitroalkenes Inhibit Angiotensin II Induced Hypertension And Induce Apoptosis Of Smooth Muscle Cells

Nitric oxide (NO) is an omnipresent intercellular messenger in all vertebrates, modulating blood flow, thrombosis, and neural activity. inhaling low concentrations of gaseous NO is approved by the Food and Drug Administration for the treatment of persistent pulmonary hypertension of the newborn. The production of cGMP by guanylate cyclase is the major signal transduction mechanism of NO. Only 5–10 nM NO is necessary to activate guanylate cyclase. NO can diffuse from where it is synthesized into surrounding cells where it will activate soluble guanylate cyclase in the target tissue to produce cGMP. in turn, cGMP activates cGMPdependent kinases in the target tissue that modulates intracellular calcium levels to modulate many diverse activities in the target tissues. The biochemistry of fatty acid nitration stems from the reactions of .NO, .NO-derived oxides of nitrogen .Multiple mechanisms induce biomolecule nitration, with this redundancy supporting the concept that nitration reactions transducer.NO signaling and tissue inflammatory responses.Recently, the nitroalkene derivative of linoleic acid (LNO2) was detected in human blood at concentrations (500nM), OA-NO2 regioisomers were measured in human blood and urine at levels exceeding those of LNO2, total concentration exceed 1uM, it is sufficient to induce biological responses . Nitroalkenes display potent anti-inflammatory properties as they inhibit human neutrophil superoxide generation, degranulation, and integrin expression, and they also attenuate lipopolysaccharide induced secretion of proinflammatory cytokines in cultured macrophages. Additionally, nitroalkenes are found to be a robust endogenous ligand for peroxisome proliferator-activated receptor-g (PPARg) although they also activate PPARa and PPARb at increasing concentrations. Finally, nitroalkenes exhibit other signaling properties, such as releasing nitric oxide.in addition ,Nitroalkenes can inhibit Angii induced hypertension and neointima formation after artery injury. Therefore, it gives us some clue for pharmaceutical and clinical uses.The study were composed by two: 1.it exhibited the mechanism that OA-NO2 inhibit ANgii induced hypertension.1)AT1aR mRNA was downregulated more that 60% by OA-NO2. 2) it is NO/PPARg-independent manner .3) OA-NO2 does not affect AT1aR promoter activity . 4) OA-NO2does not change the binding of ANGii and AT1aR. 5) OA-NO2 inhibit AT1aR translocation to membrane by directly binding. 2. 1) LNO2 and OA-NO2 induce RASMC apoptosis. 2) LNO2 and OA-NO2 can activate Caspase signaling . 3) LNO2 and OA-NO2 can upregulate Bad which is proapoptotic protein belongs to Bcl2 family.in conclusion, 1)The study exhibit the mechanisms of OA-NO2 inhibit ANGii induced hypertension. First is downregulate AT1aR expression transcriptionally, second is inhibit AT1aR translocation to membrane by directly binding. 2) LNO2 and OA-NO2 induce RASMC apoptosis by activate caspase 3,8,9, upregulate proapoptotic protein Bad; but P53 is upregulated by LNO2 , in contrast, OA-NO2 can downregulate P53 , Bcl-Xl and Bax. All those give us clue that they induce RASMCs apoptosis by different pathways.