Angiotensin II stimulates p21-activated kinase in vascular smooth muscle cells: role in activation of JNK.

Department of Medicine, University of Washington, Seattle 98195, USA.
Circulation Research (Impact Factor: 11.09). 07/1998; 82(12):1272-8. DOI: 10.1161/01.RES.82.12.1272
Source: PubMed

ABSTRACT Angiotensin II (Ang II) has been previously shown to stimulate the extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK) mitogen-activated protein (MAP) kinase family members. Little is known regarding the upstream signaling molecules involved in Ang II-mediated JNK activation. Ang II has been shown to activate the Janus kinase/signal transducer(s) and activator(s) of transcription (JAK/STAT) pathway, suggesting similarities to cytokine signaling. In response to cytokines such as interleukin-1 and tumor necrosis factor-alpha, the p21-activated kinase (PAK) has been identified as an upstream component in JNK activation. Therefore, we hypothesized that PAK may be involved in JNK activation by Ang II in vascular smooth muscle cells (VSMCs). AlphaPAK activity was measured by myelin basic protein phosphorylation in rat aortic VSMCs. In response to Ang II, alphaPAK was rapidly stimulated within 1 minute, with a peak (5-fold increase) at 30 minutes. AlphaPAK stimulation preceded activation of JNK in VSMCs. Ang II-mediated activation of both alphaPAK and JNK was Ca2+ dependent and inhibited by downregulation of phorbol ester-sensitive protein kinase C isoforms (by pretreatment with phorbol 12,13-dibutyrate) but not by pretreatment with GF109203X. Activation of both PAK and JNK was partially inhibited by tyrosine kinase inhibitors but not by specific Src inhibitors, suggesting regulation by a tyrosine kinase other than c-Src. Finally, introduction of dominant negative PAK markedly reduced the JNK activation by Ang II in both Chinese hamster ovary and COS cells stably expressing the Ang II type 1 receptor (AT1R). Our data provide evidence for alphaPAK as an upstream mediator of JNK in Ang II signaling and extend the role of Ang II as a proinflammatory mediator for VSMCs.

  • Source
  • [Show abstract] [Hide abstract]
    ABSTRACT: Sensory and chemical characteristics of organically and conventionally grown pac choi (often called bok choy) were identified and quantified during 18 days of shelf life storage. Sensory and instrumental data were correlated using partial least squares regression. Pac choi was grown in early autumn at the Research and Extension Center owned by Kansas State University located in Olathe, Kansas. Samples were refrigerated at 4°C and evaluated at 1, 4, 9, and 18 days after storage. Sensory analysis was conducted by a trained descriptive panel and compounds were identified and quantified using a gas chromatograph / mass spectrometer. Most of the decrease in the quality of pac choi during refrigerated storage is related to a decrease of textural attributes such as crispness and moistness as well as the increase in off-flavors such as stale/refrigerator and moldy. However, differences generally were small. Most of the flavor characteristics remained constant or varied slightly. Volatiles such as heptanal, octanal, benzeneacetaldehyde, 1-octanol, and (E)-2-nonen-1-ol generally were higher in organic pac choi, but those differences did not translate into sensory differences as none were found between the organic and conventionally grown leaves at any point in the shelf life.
    Lebensmittel-Wissenschaft und-Technologie 07/2011; 44(6):1538-1545. DOI:10.1016/j.lwt.2010.12.020 · 2.47 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Although increased amounts of reactive oxygen species in the pathogenesis of abdominal aortic aneurysm (AAA) are well documented, the precise molecular mechanisms by which reactive oxygen species induce AAAs have not been fully elucidated. This study focused on the role of hydrogen peroxide-inducible clone 5 (Hic-5), which is induced by hydrogen peroxide and transforming growth factor-β, in the cellular signaling of AAA pathogenesis. Using the angiotensin II-induced AAA model in Apoe(-/-) mice, we showed that Apoe(-/-)Hic-5(-/-) mice were completely protected from AAA formation and aortic rupture, whereas Apoe(-/-) mice were not. These features were similarly observed in smooth muscle cell-specific Hic-5-deficient mice. Furthermore, angiotensin II treatment induced Hic-5 expression in a reactive oxygen species-dependent manner in aortic smooth muscle cells in the early stage of AAA development. Mechanistic studies revealed that Hic-5 interacted specifically with c-Jun N-terminal kinase p54 and its upstream regulatory molecule mitogen-activated protein kinase kinase 4 as a novel scaffold protein, resulting in the expression of membrane type 1 matrix metalloproteinase and matrix metalloproteinase 2 activation in aortic smooth muscle cells. Hic-5 serves as a novel scaffold protein that specifically activates the mitogen-activated protein kinase kinase 4/p54 c-Jun N-terminal kinase pathway, thereby leading to the induction and activation of matrix metalloproteinases in smooth muscle cells and subsequent AAA formation. Our study provided a novel therapeutic option aimed at inhibiting the mitogen-activated protein kinase kinase 4-Hic-5-p54 c-Jun N-terminal kinase pathway in the vessel wall, particularly through Hic-5 inhibition, which may be used to produce more precise and effective therapies.
    Journal of the American Heart Association 04/2014; 3(3):e000747. DOI:10.1161/JAHA.113.000747