Lu X, Murphy TC, Nanes MS, Hart CM. PPAR␥ regulates hypoxia-induced Nox4 expression in human pulmonary artery smooth muscle cells through NF-B. Am J Physiol Lung Cell Mol Physiol 299: L559 -L566, 2010. First published July 9, 2010; doi:10.1152/ajplung.00090.2010.-NADPH oxidases are a major source of superoxide production in the vasculature. The constitutively active Nox4 subunit, which is selectively upregulated in the lungs of human subjects and experimental animals with pulmonary hypertension, is highly expressed in vascular wall cells. We demonstrated that rosiglitazone, a synthetic agonist of the peroxisome proliferatoractivated receptor-␥ (PPAR␥), attenuated hypoxia-induced pulmonary hypertension, vascular remodeling, Nox4 induction, and reactive oxygen species generation in the mouse lung. The current study examined the molecular mechanisms involved in PPAR␥-regulated, hypoxia-induced Nox4 expression in human pulmonary artery smooth muscle cells (HPASMC). Exposing HPASMC to 1% oxygen for 72 h increased Nox4 gene expression and H 2O2 production, both of which were reduced by treatment with rosiglitazone during the last 24 h of hypoxia exposure or by treatment with small interfering RNA (siRNA) to Nox4. Hypoxia also increased HPASMC proliferation as well as the activity of a Nox4 promoter luciferase reporter, and these increases were attenuated by rosiglitazone. Chromatin immunoprecipitation assays demonstrated that hypoxia increased binding of the NF-B subunit, p65, to the Nox4 promoter and that binding was attenuated by rosiglitazone treatment. The role of NF-B in Nox4 regulation was further supported by demonstrating that overexpression of p65 stimulated Nox4 promoter activity, whereas siRNA to p50 or p65 attenuated hypoxic stimulation of Nox4 promoter activity. These results provide novel evidence for NF-B-mediated stimulation of Nox4 expression in HPASMC that can be negatively regulated by PPAR␥. These data provide new insights into potential mechanisms by which PPAR␥ activation inhibits Nox4 upregulation and the proliferation of cells in the pulmonary vascular wall to ameliorate pulmonary hypertension and vascular remodeling in response to hypoxia. nuclear factor-B; peroxisome proliferator-activated receptor-␥ NADPH OXIDASES ARE A MAJOR source of superoxide production in the vasculature that contributes to endothelial dysfunction and vascular cell proliferation (4,19). In nonphagocytic cells, the catalytic moiety of NADPH oxidases is composed of one or more gp91 phox (Nox2) homologs, Nox1, -3, -4, or -5, Duox1, or Duox2 (27). These Nox homologs associate with the membrane-bound p22 phox subunit to generate reactive oxygen species (ROS). Nox4 is highly expressed in vascular wall cells including smooth muscle and endothelial cells (47). In contrast to the other Nox homologs, current evidence indicates that Nox4 is constitutively active (1), and increases in Nox4 mRNA levels increase Nox4 activity (45). Nox4 expression is increased by diverse stimuli (4) including E2F transcription factors, serum starvati...

Persistent, dominant, and large‐amplitude gravity waves with 3–10 h periods and vertical wavelengths ~20–30 km are observed in temperatures from the stratosphere to lower thermosphere with an Fe Boltzmann lidar at McMurdo, Antarctica. These waves exhibit characteristics of inertia‐gravity waves in case studies, yet they are extremely persistent and have been present during every lidar observation. We characterize these 3–10 h waves in the mesosphere and lower thermosphere using lidar temperature data in June from 2011 to 2015. A new method is applied to identify the major wave events from every lidar run longer than 12 h. A continuous 65 h lidar run on 28–30 June 2014 exhibits a 7.5 h wave spanning ~60 h, and 6.5 h and 3.4 h waves spanning 40 and 45 h, respectively. Over the course of 5 years, 323 h of data in June reveal that the major wave periods occur in several groups centered from ~3.5 to 7.5 h, with vertical phase speeds of 0.8–2 m/s. These 3–10 h waves possess more than half of the spectral energy for ~93% of the time. A rigorous prewhitening, postcoloring technique is introduced for frequency power spectra investigation. The resulting spectral slopes are unusually steep (−2.7) below ~100 km but gradually become shallower with increasing altitude, reaching about −1.6 at 110 km. Two‐dimensional fast Fourier transform spectra confirm that these waves have a uniform dominant vertical wavelength of 20–30 km across periods of 3.5–10 h. These statistical features shed light on the wave source and pave the way for future research.

[1] This study presents the first coincident observation of inertia-gravity waves (IGWs) by lidar and radar in the Antarctic mesopause region. This is also the first known observation of two simultaneous IGWs at the same location. An Fe Boltzmann lidar at Arrival Heights (77.8 S, 166.7 E) provides high-resolution temperature data, and a co-located MF radar provides wind data. On 29 June 2011, coherent wave structures are observed in both the Fe lidar temperature and MF radar winds. Two dominant waves are determined from the temperature data with apparent periods of 7.7 AE 0.2 and 5.0 AE 0.1 h and vertical wavelengths of 22 AE 2 and 23 AE 2 km, respectively. The simultaneous measurements of temperature and wind allow the intrinsic wave properties to be derived from hodograph analyses unambiguously. The analysis shows that the longer-period wave propagates northward with an azimuth of θ = 11 AE 5 clockwise from north. This wave has a horizontal wavelength of l h = 2.2 AE 0.2 Â 10 3 km and an intrinsic period of t I = 7.9 AE 0.3 h. The intrinsic horizontal phase speed (C Ih ) for this wave is 80 AE 4 m/s, while the horizontal and vertical group velocities (C gh and C gz ) are 48 AE 3 m/s and 0.5 AE 0.1 m/s, respectively. The shorter-period wave has t I = 4.5 AE 0.3 h and θ = 100 AE 4 with l h = 1.1 AE 0.1 Â 10 3 km and C Ih = 68 AE 5 m/s. Its group velocities are C gh = 58 AE 5 m/s and C gz = 1.1 AE 0.1 m/s. Therefore, both waves propagate with very shallow elevation angles from the horizon (f = 0.6 AE 0.1 and f = 1.1 AE 0.1 for the longer-and shorter-period waves, respectively) but originate from different sources. Our analysis suggests that the longer-period IGW most likely originates from the stratosphere in a region of unbalanced flow.

Osteoblast (OB) differentiation is suppressed by tumor necrosis factor-␣ (TNF-␣), an inflammatory stimulus that is elevated in arthritis and menopause. Because OB differentiation requires the expression of the transcription factor osterix (Osx), we investigated TNF effects on Osx. TNF inhibited Osx mRNA in pre-osteoblastic cells without affecting Osx mRNA half-life. Inhibition was independent of new protein synthesis. Analysis of the Osx promoter revealed two transcription start sites that direct the expression of an abundant mRNA (Osx1) and an alternatively spliced mRNA (Osx2). Promoter fragments driving the expression of luciferase were constructed to identify TNF regulatory sequences. Two independent promoters were identified upstream of each transcription start site. TNF potently inhibited transcription of both promoters. Deletion and mutational analysis identified a TNF-responsive region proximal to the Osx2 start site that retained responsiveness when inserted upstream of a heterologous promoter. The TNF response region was a major binding site for nuclear proteins, although TNF did not change binding at the site. The roles of MAPK and NFB were investigated as signal mediators of TNF. Inhibitors of MEK1 and ERK1, but not of JNK or p38 kinase, abrogated TNF inhibition of Osx mRNA and promoter activity. TNF action was not prevented by blockade of NFB nuclear entry. The forced expression of high levels of NFB uncovered a proximal promoter enhancer; however, this site was not activated by TNF. The inhibitory effect of TNF on Osx expression may decrease OB differentiation in arthritis and osteoporosis. Osteoblasts (OBs)2 are derived from pluripotent precursor cells of mesenchymal origin that are capable of differentiation to chondrocytes, myocytes, adipocytes, or fibroblasts (1). Bone formation in the embryo and remodeling in the adult require that a sufficient number of precursor cells differentiate to functional OBs. New OBs are continuously required for the synthesis of bone matrix and replacement of cells becoming osteocytes or undergoing apoptosis. A coordinated expression of transcription factors determines the commitment of precursor cells toward the OB phenotype under the control of autocrine, paracrine, and hormonal stimuli. Two of these transcription factors, RUNX2 (Cbfa1/AML3/Pebp2␣A) and Osx, are required for differentiation to the OB lineage. In mice, RUNX2 gene knock-out causes a lethal mutation with a cartilaginous skeleton. RUNX2 is presumed to function as an organizer on promoters of skeletal-specific genes (2). A phenotype similar to the RUNX2 knock-out is observed with knock-out of Osx. Here the arrest in development occurs slightly later but also results in a cartilaginous skeleton (3). In addition, Osx induces OB differentiation of dispersed embryonic cells (4). RUNX2 is expressed in Osx knock-outs, suggesting that Osx functions downstream of RUNX2 in the differentiation pathway.Differentiation of precursor cells to OBs in adult bone is impaired by inflammatory stimuli. In rheumatoid arthri...