Endothelin (ET)-1 is a well-known cardiac hypertrophic factor.
Eicosapentaenoic acid (EPA) prevents endothelin-1-induced cardiomyocyte hypertrophy.
vitamin C downregulates TNF-alpha-induced ICAM-1 expression via the inhibition of NF-kappaB activation
nitric oxide and endothelin-1, the yin and yang on vascular function
NO is a more potent inhibitor of ET-1-mediated elevated arterial pressure(/airway smooth muscle cell) than other pressor pathways, due in part to inhibition of intravascular pressure-independent release of ET-1.
vitamin c is a booster of NO synthase
nitrates and nitrites are precusor of NO.
Prostaglandins Leukot Essent Fatty Acids. 2015 Jun; 97: 27¨C34.
Published online 2015 Apr 11. doi: 10.1016/j.plefa.2015.03.002
Docosahexaenoic acid(DHA) differentially affects TNF¦Á and IL-6 expression in LPS-stimulated RAW 264.7 murine macrophages
Kaori L. Honda, Stefania Lamon-Fava, Nirupa R. Matthan, Dayong Wu, and Alice H. Lichtenstein*
Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111, USA
Docosahexaenoic acid (DHA) is generally reported to have anti-inflammatory properties, however, prior work has documented differential effects on individual pro-inflammatory cytokines: reduced IL-6, but not TNF¦Á, mRNA expression in macrophages. To elucidate the mechanism, the roles of prostaglandin E2 (PGE2), cyclic AMP response element-binding protein (CREB), and NF¦ÊB were examined in RAW 264.7 macrophages. DHA did not influence CREB activity, but significantly reduced PGE2 production by 41% and NF¦ÊB activity by 32%. Exogenous PGE2 inhibited TNF¦Á mRNA expression dose dependently. Unexpectedly, inhibiting PGE2 production with NS-398 also decreased TNF¦Á mRNA expression, suggesting a concentration-dependent dual role of PGE2 in regulating TNF¦Á expression. IL-6 expression was unaffected by endogenous or exogenous PGE2. Partial block of NF¦ÊB activation (SN50; 46%, or, BAY-11-7082; 41%) lowered IL-6 to a greater extent than TNF¦Á mRNA expression. The differential effect of DHA on TNF¦Á and IL-6 mRNA expression may be mediated via reduction in NF¦ÊB activity.
Keywords: TNF¦Á, IL-6, TLR4, Macrophages, PGE2, CREB
Docosahexaenoic acid differentially affects TNF¦Á and IL-6 expression in LPS-stimulated RAW 264.7 murine macrophages
TNF¦Á-induced airway smooth muscle cell proliferation depends on endothelin receptor signaling, GM-CSF and IL-6
Pathological proliferation of human airway smooth muscle cells (HASMCs) causes hyperplasia in chronic lung diseases. Signaling pathways that link airway inflammation to HASMC proliferation might provide therapeutic targets for the prevention of airway remodeling and chronic lung diseases. Endothelin-1 (ET-1) signals via endothelin-A- and B-receptors (ETAR, ETBR) to perpetuate HASMC-associated and TNF¦Á-dependent inflammatory processes.
Hypothesis: endothelin receptor antagonists (ERAs) suppress HASMC proliferation induced by inflammatory cytokines. HASMCs were stimulated ex vivo with cytokines in the presence or absence of ERAs (ETAR-specific/selective: BQ123, ambrisentan; ETBR-specific: BQ788; non-selective: bosentan, macitentan, ACT-132577) or cytokine-blocking antibodies. Cell counts, DNA-synthesis (BrdU-incorporation assay), cytokine production (ELISA) and ETBR expression (whole-genome microarray data, western blot) were analyzed.
ET-1-induced HASMC proliferation and DNA-synthesis were reduced by protein kinase inhibitors and ETAR-specific/selective ERAs but not by BQ788. TNF¦Á-induced HASMC proliferation and DNA-synthesis were reduced by all ERAs. TNF¦Á induced ET-1 and ETBR expression. TNF¦Á- and ET-1-induced GM-CSF releases were both reduced by BQ123 and BQ788. TNF¦Á- and ET-1-induced IL-6 releases were both reduced by BQ123 but not by BQ788. Combined but not single blockade of GM-CSF-receptor-¦Á-chain and IL-6 reduced TNF¦Á- and ET-1-induced HASMC proliferation and DNA-synthesis. Combined but not single treatment with GM-CSF and IL-6 induced HASMC proliferation and DNA-synthesis in the presence of ET-1.
In conclusion, TNF¦Á induces HASMC proliferation via ET-1/GM-CSF/IL-6. ETBR requires up-regulation by TNF¦Á to mediate ET-1 effects on HASMC proliferation. This signaling cascade links airway inflammation to HASMC-associated remodeling processes and is sensitive to ERAs. Therefore, ERAs could prevent inflammation-induced airway smooth muscle hyperplasia.
TNF¦Á-induced airway smooth muscle cell proliferation depends on endothelin receptor signaling, GM-CSF and IL-6 - ScienceDirect
Eicosapentaenoic acid prevents endothelin-1-induced cardiomyocyte hypertrophy in vitro through the suppression of TGF-¦Â1 and phosphorylated JNK
Nobutake Shimojo, Subrina Jesmin, Sohel Zaedi, Seiji Maeda, Masaaki Soma,
The cardiovascular benefit of fish oil in humans and experimental animals has been reported. Endothelin (ET)-1 is a well-known cardiac hypertrophic factor. However, although many studies link a fish oil extract, eicosapentaenoic acid (EPA), to cardiac protection, the effects of EPA on cardiac hypertrophy and underlying mechanism(s) are unclear. The present study investigated whether EPA prevents ET-1-induced cardiomyocyte hypertrophy; the potential pathways likely to underlie such an effect were also investigated. Cardiomyocytes were isolated from neonatal rat heart, cultured for 3 days, and then treated for 24 h with vehicle only (control), treated with 0.1 nM ET-1 only, or pretreated with 10 ¦ÌM EPA and then treated with 0.1 nM ET-1. The cells were harvested, and changes in cell surface area, protein synthesis, expression of a cytoskeletal (¦Á-actinin) protein, and cell signaling were analyzed. ET-1 induced a 97% increase in cardiomyocyte surface area, a 72% increase in protein synthesis rate, and an increase in expression of ¦Á-actinin and signaling molecule [transforming growth factor-¦Â1 (TGF-¦Â1), c-Jun NH2-terminal kinase (JNK), and c-Jun]. Development of these ET-1-induced cellular changes was attenuated by EPA. Moreover, the hypertrophied cardiomyocytes showed a 1.5- and a 1.7-fold increase in mRNA expression of atrial and brain natriuretic peptides, the classical molecular markers of cardiac hypertrophy, respectively; these changes were also suppressed by EPA. Here we show that ET-1 induces cardiomyocyte hypertrophy and expression of hypertrophic markers, possibly mediated by JNK and TGF-¦Â1 signaling pathways. These ET-1-induced effects were blocked by EPA, a major fish oil ingredient, suggesting that fish oil may have beneficial protective effects on cardiac hypertrophy.
Eicosapentaenoic acid prevents endothelin-1-induced cardiomyocyte hypertrophy in vitro through the suppression of TGF-¦Â1 and phosphorylated JNK | American Journal of Physiology-Heart and Circulatory Physiology
Arch Pharm Res . 2004 Oct; 27(10):1073-9.
Vitamin C blocks TNF-alpha-induced NF-kappaB activation and ICAM-1 expression in human neuroblastoma cells
Eun-Wha Son 1, Sung-Ji Mo, Dong-Kwon Rhee, Suhkneung Pyo
Interactions of the cell adhesion molecules are known to play important roles in mediating inflammation. The proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), activates the NF-kappaB signaling pathway, which induces the expression of various genes, such as intercellular adhesion molecule-1 (ICAM-1). In this study, the effect of vitamin C on the ICAM-1 expression induced by TNF-alpha in a human neuroblastoma cell line, SK-N-SH was investigated. Treatment with vitamin C resulted in the downregulation of the TNF-alpha-induced surface expression and ICAM-1 mRNA levels in a concentration-dependent manner. Moreover, a gel shift analysis indicated that vitamin C dose-dependently inhibited the NF-kappaB activation and IkappaBalpha degradation induced by TNF-alpha.
Taken together, these results suggest that vitamin C downregulates TNF-alpha-induced ICAM-1 expression via the inhibition of NF-kappaB activation.
Vitamin C blocks TNF-alpha-induced NF-kappaB activation and ICAM-1 expression in human neuroblastoma cells - PubMed