Endothelial Dysfunction and Vascular Inflammation

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Abstract

Transfection of monoblastoid U937 cells with human eNOS resulted in a cell line that produces NO in response to a calcium ionophore, but little or no NO in the resting state (Blood, 1997). However, after differentiation with phorbol-12-acetate-13-myristate, eNOS expressing cells produced increased amounts of both TNFalpha and reactive oxygen species by mechanisms that were independent of NO.[unreadable] [unreadable] Neither N-omega-methyl-L-arginine, a NOS inhibitor, nor mutation of the L-arginine binding site of eNOS (rendering it incapable of producing nitric oxide) blocked the ability of eNOS to upregulate TNFalpha (J Biol Chem, 2000). Conversely, co-transfection with superoxide dismutare or deletion of the NADPH binding site of eNOS completely prevented eNOS from upregulating TNFalpha production. These results suggest that eNOS can regulate inflammatory responses through both NO (J Immunol, 1994; J Biol Chem, 1997) and reactive oxygen species-based signal transduction pathways (J Biol Chem, 2000).[unreadable] [unreadable] Superoxide produced by eNOS was shown to upregulate TNFalpha via p42/44 MAPK activation (J Biol Chem, 2001).[unreadable] [unreadable] Sp1 was shown to act as a NO sensor, down regulating eNOS in endothelial cells via a proximal Sp promoter-binding site (J Biol Chem, 2003).[unreadable] [unreadable] Sickle cell disease was characterized by oxidant and inflammatory stress in the vasculature, even in the absence of an acute crisis (Blood, 2004). Circulatory stress in sickle cell disease was associated with gene expression and arginine metabolism abnormalities in platelets (Circulation, 2007)[unreadable] [unreadable] Anti-proliferative effects of NO that prevent the development of a chronic vascular injury phenotype was linked to p38 MAPK activation and p21 mRNA stabilization with subsequent down regulation of polo-like kinase 1 through a CDE/CHR proximal promoter site (BMC Genomics, 2005; J Biol Chem, 2006).[unreadable] [unreadable] Both NO and peroxisome proliferator-activated receptors (PPARs) protect the endothelium and regulate its function. Therefore, we tested for crosstalk between these signaling pathways using human umbilical vein and hybrid EA.hy926 endothelial cells (FASEB J, 2007). PPARgamma was activated by NO through a p38 MAPK dependent signal transduction pathway. This crosstalk mechanism may contribute to the anti-inflammatory and cytoprotective effects of NO in the vasculature and suggests new strategies for preventing and treating vascular dysfunction.