It has been established that PPAR�� can physically bind to NF-��B enzyme inhibitor p65 and suppress NF-��B (7, 43, 52, 55). More limited evidence suggests that NF-��B p65 and PPAR�� are mutually repressive and antagonize the transcriptional activity of each other. This concept is consistent with our (26) recent finding that enhanced NF-��B activity was observed in the aortas of endothelial PPAR�� knockout mice. As shown in Fig. 3, in silico analysis of the Nox4 promoter reveals several PPRE in the vicinity of NF-��B binding sites that could potentially regulate Nox4 promoter activity. We speculate that rosiglitazone stimulates PPAR�� binding to PPRE sites on the Nox4 promoter, physically preventing NF-��B from binding to adjacent sites and thereby inhibiting Nox4 promoter activity.

This postulate is consistent with ChIP assays demonstrating that hypoxia-induced increases in p65 binding to the Nox4 promoter were attenuated by rosiglitazone. Alternatively, PPAR�� may interact with p65 before Nox4 promoter interaction (7). The specific mechanisms of these interactions remain areas of active investigation in our laboratories. Taken together, our findings provide novel evidence for NF-��B-mediated stimulation of Nox4 expression in HPASMC that can be negatively regulated by TZD PPAR�� ligands. Based on evidence that Nox4 participates in both hypoxia-induced pulmonary hypertension in mice and in human pulmonary arterial hypertension (37), these findings suggest that PPAR�� may represent a new therapeutic target in pulmonary hypertension.

Our results provide new insights into potential mechanisms by which PPAR�� activation inhibits Nox4 upregulation and the proliferation of cells in the pulmonary vascular wall cell to ameliorate pulmonary hypertension and vascular remodeling in response to hypoxia. Additional in vivo studies will be needed to confirm these findings that may provide a basis for the development of novel treatment strategies for pulmonary hypertension. GRANTS This work was supported by funding from the Research Service of the Atlanta Veterans Affairs Medical Center (C. M. Hart and M. S. Nanes) and by National Institute of Diabetes and Digestive Batimastat and Kidney Diseases Grant DK-074518 (C. M. Hart). DISCLOSURES No conflicts of interest, financial or otherwise, are declared by the author(s).
acid-sensing ion channels (ASICs) are activated by extracellular protons and belong to the epithelial Na+ channel (ENaC)/degenerin (Deg) family of ion channels. Four ASIC genes (ASIC1�CASIC4) have been cloned, and ASIC1�CASIC3 have splice variants (19, 28, 29, 31, 42). ASICs are permeable to Na+ but also to other monovalent and divalent cations like Ca2+ (in the case of ASIC1), Li+, K+, and H+ (41, 42).