Endothelial Nitric-oxide Synthase Enhances Lipopolysaccharide-stimulated Tumor Necrosis Factor-α Expression via cAMP-mediated p38 MAPK Pathway in Cardiomyocytes

The purpose of this study was to investigate the role of endothelial nitric-oxide synthase (eNOS), cAMP, and p38 MAPK in tumor necrosis factor-α (TNF-α) expression induced by lipopolysaccharide (LPS). LPS dose- and time-dependently induced phosphorylation of p38 MAPK and TNF-α expression in neonatal mouse cardiomyocytes. TNF-α expression was preceded by p38 MAPK phosphorylation, and selective inhibition of p38 MAPK abrogated LPS-induced TNF-α expression. Deficiency in eNOS decreased basal and LPS-stimulated TNF-α expression in cardiomyocytes. NOS inhibitorl-NAME attenuated LPS-induced p38 MAPK phosphorylation and TNF-α production in wild-type cardiomyocytes, whereas NO donor 2,2′-(hydroxynitrosohydrazono)bis-ethanamine (DETA-NO) (2 μm) or overexpression of eNOS by adenoviral gene transfer restored the response of eNOS−/−cardiomyocytes to LPS. These effects of NO were mediated through cAMP-dependent pathway based on the following facts. First, deficiency in eNOS decreased basal levels of intracellular cAMP, and DETA-NO elevated intracellular cAMP levels in eNOS−/−cardiomyocytes. Second, a cAMP analogue 8-Br-cAMP mimicked the effect of NO in eNOS−/− cardiomyocytes. Third, either inhibition of cAMP or cAMP-dependent protein kinase attenuated LPS-stimulated p38 MAPK phosphorylation and TNF-α production in wild-type cardiomyocytes. In conclusion, eNOS enhances LPS-stimulated TNF-α expression in cardiomyocytes. Activation of p38 MAPK is essential in LPS-stimulated TNF-α expression. Moreover, the effects of NO on LPS-stimulated TNF-α expression are mediated through cAMP/cAMP-dependent protein kinase-dependent p38 MAPK pathway in neonatal cardiomyocytes. The purpose of this study was to investigate the role of endothelial nitric-oxide synthase (eNOS), cAMP, and p38 MAPK in tumor necrosis factor-α (TNF-α) expression induced by lipopolysaccharide (LPS). LPS dose- and time-dependently induced phosphorylation of p38 MAPK and TNF-α expression in neonatal mouse cardiomyocytes. TNF-α expression was preceded by p38 MAPK phosphorylation, and selective inhibition of p38 MAPK abrogated LPS-induced TNF-α expression. Deficiency in eNOS decreased basal and LPS-stimulated TNF-α expression in cardiomyocytes. NOS inhibitorl-NAME attenuated LPS-induced p38 MAPK phosphorylation and TNF-α production in wild-type cardiomyocytes, whereas NO donor 2,2′-(hydroxynitrosohydrazono)bis-ethanamine (DETA-NO) (2 μm) or overexpression of eNOS by adenoviral gene transfer restored the response of eNOS−/−cardiomyocytes to LPS. These effects of NO were mediated through cAMP-dependent pathway based on the following facts. First, deficiency in eNOS decreased basal levels of intracellular cAMP, and DETA-NO elevated intracellular cAMP levels in eNOS−/−cardiomyocytes. Second, a cAMP analogue 8-Br-cAMP mimicked the effect of NO in eNOS−/− cardiomyocytes. Third, either inhibition of cAMP or cAMP-dependent protein kinase attenuated LPS-stimulated p38 MAPK phosphorylation and TNF-α production in wild-type cardiomyocytes. In conclusion, eNOS enhances LPS-stimulated TNF-α expression in cardiomyocytes. Activation of p38 MAPK is essential in LPS-stimulated TNF-α expression. Moreover, the effects of NO on LPS-stimulated TNF-α expression are mediated through cAMP/cAMP-dependent protein kinase-dependent p38 MAPK pathway in neonatal cardiomyocytes. tumor necrosis factor-α lipopolysaccharide mitogen-activated protein kinase nitric oxide nitric-oxide synthase endothelial nitric-oxide synthase inducible nitric-oxide synthase adenylate cyclase guanylate cyclase cAMP-dependent protein kinase N ω-nitro-l-arginine methyl ester 1H-[1,2,4]oxadiazolo[4,3-α]quinoxalin-1-one reverse transcriptase glyceraldehyde-3-phosphate dehydrogenase enzyme-linked immunosorbent assay nuclear factor-κB, DETA-NO, 2,2′-(hydroxynitrosohydrazono)bis-ethanamine Toll-like receptors S-nitroso-N-acetylpenicillamine Tumor necrosis factor-α (TNF-α),1 a pro-inflammatory cytokine with multiple biological actions (1Meldrum D.R. Am. J. Physiol. 1998; 274: R577-R595Google Scholar, 2Tracey K.J. Cerami A. Annu. Rev. Cell Biol. 1993; 9: 317-343Google Scholar), impairs contractile function in intact animals, isolated hearts, and cardiomyocytes (3Bozkurt B. Kribbs S.B. Clubb Jr., F.J. Michael L.H. Didenko V.V. Hornsby P.J. Seta Y. Oral H. Spinale F.G. Mann D.L. Circulation. 1998; 97: 1382-1391Google Scholar, 4Grandel U. Fink L. Blum A. Heep M. Buerke M. Kraemer U. Circulation. Scholar, H. Mann D.L. J. Biol. The TNF-α is to production to of L. Mann D.L. J. 1993; The TNF-α is mediated by and inhibition of dehydrogenase and function B. H. M. J. Scholar, In to the of TNF-α of with in a by H. H. H. H. M. Circulation. Deficiency in TNF-α function Michael L.H. Mann D.L. U. A. 97: These TNF-α a role in and of a in TNF-α in response to LPS U. Fink L. Blum A. Heep M. Buerke M. Kraemer U. Circulation. Scholar, J. Mann D.L. J. the of LPS-induced TNF-α expression in cardiomyocytes on Toll-like receptors A. Mann D.L. Am. J. Physiol. Scholar, Mann D.L. J. Scholar, P.J. Jr., Am. J. Physiol. and nuclear in cardiomyocytes P.J. Jr., Am. J. Physiol. Scholar, P.J. Jr., is the of and of role of p38 MAPK in TNF-α expression induced by LPS in J. p38 MAPK is in LPS-stimulated TNF-α expression in cardiomyocytes to synthase a of of expression and the of nitric oxide Rev. Scholar, U. M. H. nitric-oxide synthase is in and Y. Rev. nitric-oxide synthase is or cytokine and levels of NO to or tumor Scholar, Rev. Scholar, D.L. J. Circulation. nitric-oxide synthase is in a of endothelial and cardiomyocytes. Activation of eNOS levels of a of of inhibition of and of function Rev. Scholar, Scholar, M. H. M. J. 1998; These actions of NO to either the production of guanylate cyclase and of protein kinase or the production of cAMP adenylate cyclase and of cAMP-dependent protein kinase in cardiomyocytes A. J. Scholar, Seta Y. Mann D.L. Circulation. NO to TNF-α production in and in the Seta Y. Mann D.L. Circulation. Scholar, L. J. Biol. NO eNOS TNF-α expression LPS in purpose of this study was to investigate the role of eNOS in of TNF-α expression LPS and to the of p38 cAMP to LPS-induced TNF-α expression in neonatal mouse of the study are NO production eNOS basal and LPS-stimulated TNF-α expression in neonatal mouse cardiomyocytes. TNF-α expression was preceded by phosphorylation of p38 and selective inhibition of p38 MAPK abrogated TNF-α expression by role of p38 MAPK in LPS-induced TNF-α expression. the effects of NO were mediated through the p38 MAPK study a by NO eNOS LPS-stimulated TNF-α expression in eNOS LPS-induced TNF-α cAMP-dependent role in the of function In the study NO LPS-stimulated TNF-α expression in neonatal mouse cardiomyocytes. was based on the following of First, deficiency in eNOS decreased basal and LPS-stimulated TNF-α and protein expression in mouse cardiomyocytes. Second, of NOS in wild-type cardiomyocytes decreased LPS-induced TNF-α expression to the to of eNOS−/− cardiomyocytes. Third, either NO donor DETA-NO or was to LPS-stimulated TNF-α production in eNOS−/−cardiomyocytes to a of wild-type cardiomyocytes. In the TNF-α was LPS was is with of in cardiomyocytes or of LPS U. Fink L. Blum A. Heep M. Buerke M. Kraemer U. Circulation. Scholar, P.J. Jr., In deficiency in the response to LPS in of TNF-α production in cardiomyocytes. the of in LPS-induced TNF-α expression is in the of NO are mediated by and A. J. study Seta Y. Mann D.L. Circulation. NO induced TNF-α expression in cardiomyocytes the in the study to the effects of NO on TNF-α expression in eNOS−/−cardiomyocytes. abrogated NO production TNF-α in wild-type cardiomyocytes in response to LPS. The the effect of NO on LPS-stimulated TNF-α expression is of in cardiomyocytes. effects of NO on LPS-induced TNF-α expression in L. P.J. J. levels of NO and cAMP by a in cardiomyocytes A. J. with this DETA-NO intracellular cAMP levels in eNOS−/− cardiomyocytes. Moreover, deficiency in eNOS decreased cAMP levels in cardiomyocytes. the effects of NO on LPS-induced TNF-α production were mediated through in cardiomyocytes. of cAMP production attenuated LPS-induced TNF-α expression in wild-type cardiomyocytes. cAMP analogue 8-Br-cAMP mimicked the effects of NO by TNF-α production in eNOS−/− cardiomyocytes. These were D.R. A. B. 1998; cAMP LPS-induced TNF-α expression in cardiomyocytes. is to the of cAMP in cardiomyocytes is protein A. J. the of cAMP, of cAMP analogue and in the levels of cAMP basal LPS-induced TNF-α cAMP effects on intracellular in cardiomyocytes. of cAMP analogue LPS-induced TNF-α levels of cAMP LPS-induced TNF-α expression in of p38 MAPK LPS-induced TNF-α in the study is LPS-stimulated TNF-α expression is mediated through p38 MAPK in neonatal cardiomyocytes. LPS-induced phosphorylation of p38 MAPK was a preceded the of TNF-α inhibition of p38 MAPK abrogated TNF-α expression induced by LPS. The by LPS phosphorylation of p38 MAPK in cardiomyocytes is LPS p38 MAPK by protein through M. P.J. J. 1998; and Mann D.L. J. Scholar), and by through pathway L. Jr., J. Biol. eNOS LPS-stimulated p38 MAPK Activation M. B. J. Biol. cAMP p38 MAPK a in mouse cardiomyocytes. protein and p38 MAPK J. M. Am. J. Physiol. Scholar, M. Cell Biol. is p38 MAPK is the effects of NO on LPS-induced TNF-α expression. In the inhibition of either NOS or attenuated LPS-induced phosphorylation of p38 MAPK and TNF-α in cardiomyocytes. of a NO donor or a cAMP analogue phosphorylation of p38 MAPK and TNF-α induced by LPS in eNOS−/− cardiomyocytes. inhibition of decreased phosphorylation of p38 MAPK and TNF-α expression induced by LPS. NO enhances LPS-induced p38 MAPK and TNF-α expression a the study the NO eNOS enhances LPS-stimulated TNF-α expression in neonatal mouse cardiomyocytes. Activation of p38 MAPK is essential in LPS-stimulated TNF-α expression. Moreover, the effects of NO on LPS-stimulated TNF-α expression are mediated through p38 MAPK These to LPS of TNF-α in cardiomyocytes. The of the NO enhances LPS-induced TNF-α expression in cardiomyocytes in is levels of TNF-α to effects on TNF-α is to K.J. Cerami A. Annu. Rev. Cell Biol. 1993; 9: 317-343Google is expression of TNF-α by eNOS to of response in the in the of and to the of the the are TNF-α expression to expression Biol. and eNOS of TNF-α production the of the MAPK pathway in Tumor necrosis factor-α (TNF-α),1 a pro-inflammatory cytokine with multiple biological actions (1Meldrum D.R. Am. J. Physiol. 1998; 274: R577-R595Google Scholar, 2Tracey K.J. Cerami A. Annu. Rev. Cell Biol. 1993; 9: 317-343Google Scholar), impairs contractile function in intact animals, isolated hearts, and cardiomyocytes (3Bozkurt B. Kribbs S.B. Clubb Jr., F.J. Michael L.H. Didenko V.V. Hornsby P.J. Seta Y. Oral H. Spinale F.G. Mann D.L. Circulation. 1998; 97: 1382-1391Google Scholar, 4Grandel U. Fink L. Blum A. Heep M. Buerke M. Kraemer U. Circulation. Scholar, H. Mann D.L. J. Biol. The TNF-α is to production to of L. Mann D.L. J. 1993; The TNF-α is mediated by and inhibition of dehydrogenase and function B. H. M. J. Scholar, In to the of TNF-α of with in a by H. H. H. H. M. Circulation. Deficiency in TNF-α function Michael L.H. Mann D.L. U. A. 97: These TNF-α a role in and of a in TNF-α in response to LPS U. Fink L. Blum A. Heep M. Buerke M. Kraemer U. Circulation. Scholar, J. Mann D.L. J. the of LPS-induced TNF-α expression in cardiomyocytes on Toll-like receptors A. Mann D.L. Am. J. Physiol. Scholar, Mann D.L. J. Scholar, P.J. Jr., Am. J. Physiol. and nuclear in cardiomyocytes P.J. Jr., Am. J. Physiol. Scholar, P.J. Jr., is the of and of role of p38 MAPK in TNF-α expression induced by LPS in J. p38 MAPK is in LPS-stimulated TNF-α expression in cardiomyocytes to synthase a of of expression and the of nitric oxide Rev. Scholar, U. M. H. nitric-oxide synthase is in and Y. Rev. nitric-oxide synthase is or cytokine and levels of NO to or tumor Scholar, Rev. Scholar, D.L. J. Circulation. nitric-oxide synthase is in a of endothelial and cardiomyocytes. Activation of eNOS levels of a of of inhibition of and of function Rev. Scholar, Scholar, M. H. M. J. 1998; These actions of NO to either the production of guanylate cyclase and of protein kinase or the production of cAMP adenylate cyclase and of cAMP-dependent protein kinase in cardiomyocytes A. J. Scholar, Seta Y. Mann D.L. Circulation. NO to TNF-α production in and in the Seta Y. Mann D.L. Circulation. Scholar, L. J. Biol. NO eNOS TNF-α expression LPS in cardiomyocytes. The purpose of this study was to investigate the role of eNOS in of TNF-α expression LPS and to the of p38 cAMP to LPS-induced TNF-α expression in neonatal mouse cardiomyocytes. of the study are NO production eNOS basal and LPS-stimulated TNF-α expression in neonatal mouse cardiomyocytes. TNF-α expression was preceded by phosphorylation of p38 and selective inhibition of p38 MAPK abrogated TNF-α expression by role of p38 MAPK in LPS-induced TNF-α expression. the effects of NO were mediated through the p38 MAPK study a by NO eNOS LPS-stimulated TNF-α expression in eNOS LPS-induced TNF-α cAMP-dependent role in the of function In the study NO LPS-stimulated TNF-α expression in neonatal mouse cardiomyocytes. was based on the following of First, deficiency in eNOS decreased basal and LPS-stimulated TNF-α and protein expression in mouse cardiomyocytes. Second, of NOS in wild-type cardiomyocytes decreased LPS-induced TNF-α expression to the to of eNOS−/− cardiomyocytes. Third, either NO donor DETA-NO or was to LPS-stimulated TNF-α production in eNOS−/−cardiomyocytes to a of wild-type cardiomyocytes. In the TNF-α was LPS was is with of in cardiomyocytes or of LPS U. Fink L. Blum A. Heep M. Buerke M. Kraemer U. Circulation. Scholar, P.J. Jr., In deficiency in the response to LPS in of TNF-α production in cardiomyocytes. the of in LPS-induced TNF-α expression is in the of NO are mediated by and A. J. study Seta Y. Mann D.L. Circulation. NO induced TNF-α expression in cardiomyocytes the in the study to the effects of NO on TNF-α expression in eNOS−/−cardiomyocytes. abrogated NO production TNF-α in wild-type cardiomyocytes in response to LPS. The the effect of NO on LPS-stimulated TNF-α expression is of in cardiomyocytes. effects of NO on LPS-induced TNF-α expression in L. P.J. J. levels of NO and cAMP by a in cardiomyocytes A. J. with this DETA-NO intracellular cAMP levels in eNOS−/− cardiomyocytes. Moreover, deficiency in eNOS decreased cAMP levels in cardiomyocytes. the effects of NO on LPS-induced TNF-α production were mediated through in cardiomyocytes. of cAMP production attenuated LPS-induced TNF-α expression in wild-type cardiomyocytes. cAMP analogue 8-Br-cAMP mimicked the effects of NO by TNF-α production in eNOS−/− cardiomyocytes. These were D.R. A. B. 1998; cAMP LPS-induced TNF-α expression in cardiomyocytes. is to the of cAMP in cardiomyocytes is protein A. J. the of cAMP, of cAMP analogue and in the levels of cAMP basal LPS-induced TNF-α cAMP effects on intracellular in cardiomyocytes. of cAMP analogue LPS-induced TNF-α levels of cAMP LPS-induced TNF-α expression in of p38 MAPK LPS-induced TNF-α in the study is LPS-stimulated TNF-α expression is mediated through p38 MAPK in neonatal cardiomyocytes. LPS-induced phosphorylation of p38 MAPK was a preceded the of TNF-α inhibition of p38 MAPK abrogated TNF-α expression induced by LPS. The by LPS phosphorylation of p38 MAPK in cardiomyocytes is LPS p38 MAPK by protein through M. P.J. J. 1998; and Mann D.L. J. Scholar), and by through pathway L. Jr., J. Biol. eNOS LPS-stimulated p38 MAPK Activation M. B. J. Biol. cAMP p38 MAPK a in mouse cardiomyocytes. protein and p38 MAPK J. M. Am. J. Physiol. Scholar, M. Cell Biol. is p38 MAPK is the effects of NO on LPS-induced TNF-α expression. In the inhibition of either NOS or attenuated LPS-induced phosphorylation of p38 MAPK and TNF-α in cardiomyocytes. of a NO donor or a cAMP analogue phosphorylation of p38 MAPK and TNF-α induced by LPS in eNOS−/− cardiomyocytes. inhibition of decreased phosphorylation of p38 MAPK and TNF-α expression induced by LPS. NO enhances LPS-induced p38 MAPK and TNF-α expression a the study the NO eNOS enhances LPS-stimulated TNF-α expression in neonatal mouse cardiomyocytes. Activation of p38 MAPK is essential in LPS-stimulated TNF-α expression. Moreover, the effects of NO on LPS-stimulated TNF-α expression are mediated through p38 MAPK These to LPS of TNF-α in cardiomyocytes. The of the NO enhances LPS-induced TNF-α expression in cardiomyocytes in is levels of TNF-α to effects on TNF-α is to K.J. Cerami A. Annu. Rev. Cell Biol. 1993; 9: 317-343Google is expression of TNF-α by eNOS to of response in the in the of and to the of the the are TNF-α expression to expression Biol. and eNOS of TNF-α production the of the MAPK pathway in The of the study are NO production eNOS basal and LPS-stimulated TNF-α expression in neonatal mouse cardiomyocytes. TNF-α expression was preceded by phosphorylation of p38 and selective inhibition of p38 MAPK abrogated TNF-α expression by role of p38 MAPK in LPS-induced TNF-α expression. the effects of NO were mediated through the p38 MAPK study a by NO eNOS LPS-stimulated TNF-α expression in cardiomyocytes. NO eNOS LPS-induced TNF-α cAMP-dependent role in the of function In the study NO LPS-stimulated TNF-α expression in neonatal mouse cardiomyocytes. was based on the following of First, deficiency in eNOS decreased basal and LPS-stimulated TNF-α and protein expression in mouse cardiomyocytes. Second, of NOS in wild-type cardiomyocytes decreased LPS-induced TNF-α expression to the to of eNOS−/− cardiomyocytes. Third, either NO donor DETA-NO or was to LPS-stimulated TNF-α production in eNOS−/−cardiomyocytes to a of wild-type cardiomyocytes. In the TNF-α was LPS was is with of in cardiomyocytes or of LPS U. Fink L. Blum A. Heep M. Buerke M. Kraemer U. Circulation. Scholar, P.J. Jr., In deficiency in the response to LPS in of TNF-α production in cardiomyocytes. the of in LPS-induced TNF-α expression is in the of NO are mediated by and A. J. study Seta Y. Mann D.L. Circulation. NO induced TNF-α expression in cardiomyocytes the in the study to the effects of NO on TNF-α expression in eNOS−/−cardiomyocytes. abrogated NO production TNF-α in wild-type cardiomyocytes in response to LPS. The the effect of NO on LPS-stimulated TNF-α expression is of in cardiomyocytes. effects of NO on LPS-induced TNF-α expression in L. P.J. J. levels of NO and cAMP by a in cardiomyocytes A. J. with this DETA-NO intracellular cAMP levels in eNOS−/− cardiomyocytes. Moreover, deficiency in eNOS decreased cAMP levels in cardiomyocytes. the effects of NO on LPS-induced TNF-α production were mediated through in cardiomyocytes. of cAMP production attenuated LPS-induced TNF-α expression in wild-type cardiomyocytes. cAMP analogue 8-Br-cAMP mimicked the effects of NO by TNF-α production in eNOS−/− cardiomyocytes. These were D.R. A. B. 1998; cAMP LPS-induced TNF-α expression in cardiomyocytes. is to the of cAMP in cardiomyocytes is protein A. J. the of cAMP, of cAMP analogue and in the levels of cAMP basal LPS-induced TNF-α cAMP effects on intracellular in cardiomyocytes. of cAMP analogue LPS-induced TNF-α levels of cAMP LPS-induced TNF-α expression in of p38 MAPK LPS-induced TNF-α in the study is LPS-stimulated TNF-α expression is mediated through p38 MAPK in neonatal cardiomyocytes. LPS-induced phosphorylation of p38 MAPK was a preceded the of TNF-α inhibition of p38 MAPK abrogated TNF-α expression induced by LPS. The by LPS phosphorylation of p38 MAPK in cardiomyocytes is LPS p38 MAPK by protein through M. P.J. J. 1998; and Mann D.L. J. Scholar), and by through pathway L. Jr., J. Biol. eNOS LPS-stimulated p38 MAPK Activation M. B. J. Biol. cAMP p38 MAPK a in mouse cardiomyocytes. protein and p38 MAPK J. M. Am. J. Physiol. Scholar, M. Cell Biol. is p38 MAPK is the effects of NO on LPS-induced TNF-α expression. In the inhibition of either NOS or attenuated LPS-induced phosphorylation of p38 MAPK and TNF-α in cardiomyocytes. of a NO donor or a cAMP analogue phosphorylation of p38 MAPK and TNF-α induced by LPS in eNOS−/− cardiomyocytes. inhibition of decreased phosphorylation of p38 MAPK and TNF-α expression induced by LPS. NO enhances LPS-induced p38 MAPK and TNF-α expression a the study the NO eNOS enhances LPS-stimulated TNF-α expression in neonatal mouse cardiomyocytes. Activation of p38 MAPK is essential in LPS-stimulated TNF-α expression. Moreover, the effects of NO on LPS-stimulated TNF-α expression are mediated through p38 MAPK These to LPS of TNF-α in cardiomyocytes. The of the NO enhances LPS-induced TNF-α expression in cardiomyocytes in is levels of TNF-α to effects on TNF-α is to K.J. Cerami A. Annu. Rev. Cell Biol. 1993; 9: 317-343Google is expression of TNF-α by eNOS to of response in the in the of and to the of the the are TNF-α expression to expression Biol. and eNOS of TNF-α production the of the MAPK pathway in NO eNOS LPS-induced TNF-α cAMP-dependent role in the of function In the study NO LPS-stimulated TNF-α expression in neonatal mouse cardiomyocytes. was based on the following of First, deficiency in eNOS decreased basal and LPS-stimulated TNF-α and protein expression in mouse cardiomyocytes. Second, of NOS in wild-type cardiomyocytes decreased LPS-induced TNF-α expression to the to of eNOS−/− cardiomyocytes. Third, either NO donor DETA-NO or was to LPS-stimulated TNF-α production in eNOS−/−cardiomyocytes to a of wild-type cardiomyocytes. In the TNF-α was LPS was is with of in cardiomyocytes or of LPS U. Fink L. Blum A. Heep M. Buerke M. Kraemer U. Circulation. Scholar, P.J. Jr., In deficiency in the response to LPS in of TNF-α production in cardiomyocytes. the of in LPS-induced TNF-α expression is in the of NO are mediated by and A. J. study Seta Y. Mann D.L. Circulation. NO induced TNF-α expression in cardiomyocytes the in the study to the effects of NO on TNF-α expression in eNOS−/−cardiomyocytes. abrogated NO production TNF-α in wild-type cardiomyocytes in response to LPS. The the effect of NO on LPS-stimulated TNF-α expression is of in cardiomyocytes. effects of NO on LPS-induced TNF-α expression in L. P.J. J. levels of NO and cAMP by a in cardiomyocytes A. J. with this DETA-NO intracellular cAMP levels in eNOS−/− cardiomyocytes. Moreover, deficiency in eNOS decreased cAMP levels in cardiomyocytes. the effects of NO on LPS-induced TNF-α production were mediated through in cardiomyocytes. of cAMP production attenuated LPS-induced TNF-α expression in wild-type cardiomyocytes. cAMP analogue 8-Br-cAMP mimicked the effects of NO by TNF-α production in eNOS−/− cardiomyocytes. These were D.R. A. B. 1998; cAMP LPS-induced TNF-α expression in cardiomyocytes. is to the of cAMP in cardiomyocytes is protein A. J. the of cAMP, of cAMP analogue and in the levels of cAMP basal LPS-induced TNF-α cAMP effects on intracellular in cardiomyocytes. of cAMP analogue LPS-induced TNF-α levels of cAMP LPS-induced TNF-α expression in of p38 MAPK LPS-induced TNF-α in the study is LPS-stimulated TNF-α expression is mediated through p38 MAPK in neonatal cardiomyocytes. LPS-induced phosphorylation of p38 MAPK was a preceded the of TNF-α inhibition of p38 MAPK abrogated TNF-α expression induced by LPS. The by LPS phosphorylation of p38 MAPK in cardiomyocytes is LPS p38 MAPK by protein through M. P.J. J. 1998; and Mann D.L. J. Scholar), and by through pathway L. Jr., J. Biol. eNOS LPS-stimulated p38 MAPK Activation M. B. J. Biol. cAMP p38 MAPK a in mouse cardiomyocytes. protein and p38 MAPK J. M. Am. J. Physiol. Scholar, M. Cell Biol. is p38 MAPK is the effects of NO on LPS-induced TNF-α expression. In the inhibition of either NOS or attenuated LPS-induced phosphorylation of p38 MAPK and TNF-α in cardiomyocytes. of a NO donor or a cAMP analogue phosphorylation of p38 MAPK and TNF-α induced by LPS in eNOS−/− cardiomyocytes. inhibition of decreased phosphorylation of p38 MAPK and TNF-α expression induced by LPS. NO enhances LPS-induced p38 MAPK and TNF-α expression a the study the NO eNOS enhances LPS-stimulated TNF-α expression in neonatal mouse cardiomyocytes. Activation of p38 MAPK is essential in LPS-stimulated TNF-α expression. Moreover, the effects of NO on LPS-stimulated TNF-α expression are mediated through p38 MAPK These to LPS of TNF-α in cardiomyocytes. The of the NO enhances LPS-induced TNF-α expression in cardiomyocytes in is levels of TNF-α to effects on TNF-α is to K.J. Cerami A. Annu. Rev. Cell Biol. 1993; 9: 317-343Google is expression of TNF-α by eNOS to of response in the in the of and to the of the the are TNF-α expression to expression Biol. and eNOS of TNF-α production the of the MAPK pathway in NO eNOS LPS-induced TNF-α cAMP-dependent role in the of function In the study NO LPS-stimulated TNF-α expression in neonatal mouse cardiomyocytes. was based on the following of First, deficiency in eNOS decreased basal and LPS-stimulated TNF-α and protein expression in mouse cardiomyocytes. Second, of NOS in wild-type cardiomyocytes decreased LPS-induced TNF-α expression to the to of eNOS−/− cardiomyocytes. Third, either NO donor DETA-NO or was to LPS-stimulated TNF-α production in eNOS−/−cardiomyocytes to a of wild-type cardiomyocytes. In the TNF-α was LPS was is with of in cardiomyocytes or of LPS U. Fink L. Blum A. Heep M. Buerke M. Kraemer U. Circulation. Scholar, P.J. Jr., In deficiency in the response to LPS in of TNF-α production in cardiomyocytes. the of in LPS-induced TNF-α expression is in the of NO are mediated by and A. J. study Seta Y. Mann D.L. Circulation. NO induced TNF-α expression in cardiomyocytes the in the study to the effects of NO on TNF-α expression in eNOS−/−cardiomyocytes. abrogated NO production TNF-α in wild-type cardiomyocytes in response to LPS. The the effect of NO on LPS-stimulated TNF-α expression is of in cardiomyocytes. effects of NO on LPS-induced TNF-α expression in L. P.J. J. levels of NO and cAMP by a in cardiomyocytes A. J. with this DETA-NO intracellular cAMP levels in eNOS−/− cardiomyocytes. Moreover, deficiency in eNOS decreased cAMP levels in cardiomyocytes. the effects of NO on LPS-induced TNF-α production were mediated through in cardiomyocytes. of cAMP production attenuated LPS-induced TNF-α expression in wild-type cardiomyocytes. cAMP analogue 8-Br-cAMP mimicked the effects of NO by TNF-α production in eNOS−/− cardiomyocytes. These were D.R. A. B. 1998; cAMP LPS-induced TNF-α expression in cardiomyocytes. is to the of cAMP in cardiomyocytes is protein A. J. the of cAMP, of cAMP analogue and in the levels of cAMP basal LPS-induced TNF-α cAMP effects on intracellular in cardiomyocytes. of cAMP analogue LPS-induced TNF-α levels of cAMP LPS-induced TNF-α expression in cardiomyocytes. role in the of function In the study NO LPS-stimulated TNF-α expression in neonatal mouse cardiomyocytes. was based on the following of First, deficiency in eNOS decreased basal and LPS-stimulated TNF-α and protein expression in mouse cardiomyocytes. Second, of NOS in wild-type cardiomyocytes decreased LPS-induced TNF-α expression to the to of eNOS−/− cardiomyocytes. Third, either NO donor DETA-NO or was to LPS-stimulated TNF-α production in eNOS−/−cardiomyocytes to a of wild-type cardiomyocytes. In the TNF-α was LPS was is with of in cardiomyocytes or of LPS U. Fink L. Blum A. Heep M. Buerke M. Kraemer U. Circulation. Scholar, P.J. Jr., In deficiency in the response to LPS in of TNF-α production in cardiomyocytes. the of in LPS-induced TNF-α expression is in the of NO are mediated by and A. J. study Seta Y. Mann D.L. Circulation. NO induced TNF-α expression in cardiomyocytes the in the study to the effects of NO on TNF-α expression in eNOS−/−cardiomyocytes. abrogated NO production TNF-α in wild-type cardiomyocytes in response to LPS. The the effect of NO on LPS-stimulated TNF-α expression is of in cardiomyocytes. effects of NO on LPS-induced TNF-α expression in L. P.J. J. levels of NO and cAMP by a in cardiomyocytes A. J. with this DETA-NO intracellular cAMP levels in eNOS−/− cardiomyocytes. Moreover, deficiency in eNOS decreased cAMP levels in cardiomyocytes. the effects of NO on LPS-induced TNF-α production were mediated through in cardiomyocytes. of cAMP production attenuated LPS-induced TNF-α expression in wild-type cardiomyocytes. cAMP analogue 8-Br-cAMP mimicked the effects of NO by TNF-α production in eNOS−/− cardiomyocytes. These were D.R. A. B. 1998; cAMP LPS-induced TNF-α expression in cardiomyocytes. is to the of cAMP in cardiomyocytes is protein A. J. the of cAMP, of cAMP analogue and in the levels of cAMP basal LPS-induced TNF-α cAMP effects on intracellular in cardiomyocytes. of cAMP analogue LPS-induced TNF-α levels of cAMP LPS-induced TNF-α expression in cardiomyocytes. Activation of p38 MAPK LPS-induced TNF-α in the study is LPS-stimulated TNF-α expression is mediated through p38 MAPK in neonatal cardiomyocytes. LPS-induced phosphorylation of p38 MAPK was a preceded the of TNF-α inhibition of p38 MAPK abrogated TNF-α expression induced by LPS. The by LPS phosphorylation of p38 MAPK in cardiomyocytes is LPS p38 MAPK by protein through M. P.J. J. 1998; and Mann D.L. J. Scholar), and by through pathway L. Jr., J. Biol. in the study is LPS-stimulated TNF-α expression is mediated through p38 MAPK in neonatal cardiomyocytes. LPS-induced phosphorylation of p38 MAPK was a preceded the of TNF-α inhibition of p38 MAPK abrogated TNF-α expression induced by LPS. The by LPS phosphorylation of p38 MAPK in cardiomyocytes is LPS p38 MAPK by protein through M. P.J. J. 1998; and Mann D.L. J. Scholar), and by through pathway L. Jr., J. Biol. NO eNOS LPS-stimulated p38 MAPK Activation M. B. J. Biol. cAMP p38 MAPK a in mouse cardiomyocytes. protein and p38 MAPK J. M. Am. J. Physiol. Scholar, M. Cell Biol. is p38 MAPK is the effects of NO on LPS-induced TNF-α expression. In the inhibition of either NOS or attenuated LPS-induced phosphorylation of p38 MAPK and TNF-α in cardiomyocytes. of a NO donor or a cAMP analogue phosphorylation of p38 MAPK and TNF-α induced by LPS in eNOS−/− cardiomyocytes. inhibition of decreased phosphorylation of p38 MAPK and TNF-α expression induced by LPS. NO enhances LPS-induced p38 MAPK and TNF-α expression a the study the NO eNOS enhances LPS-stimulated TNF-α expression in neonatal mouse cardiomyocytes. Activation of p38 MAPK is essential in LPS-stimulated TNF-α expression. Moreover, the effects of NO on LPS-stimulated TNF-α expression are mediated through p38 MAPK These to LPS of TNF-α in cardiomyocytes. The of the NO enhances LPS-induced TNF-α expression in cardiomyocytes in is levels of TNF-α to effects on TNF-α is to K.J. Cerami A. Annu. Rev. Cell Biol. 1993; 9: 317-343Google is expression of TNF-α by eNOS to of response in the in the of and to the of the the are TNF-α expression to expression Biol. and eNOS of TNF-α production the of the MAPK pathway in M. B. J. Biol. cAMP p38 MAPK a in mouse cardiomyocytes. protein and p38 MAPK J. M. Am. J. Physiol. Scholar, M. Cell Biol. is p38 MAPK is the effects of NO on LPS-induced TNF-α expression. In the inhibition of either NOS or attenuated LPS-induced phosphorylation of p38 MAPK and TNF-α in cardiomyocytes. of a NO donor or a cAMP analogue phosphorylation of p38 MAPK and TNF-α induced by LPS in eNOS−/− cardiomyocytes. inhibition of decreased phosphorylation of p38 MAPK and TNF-α expression induced by LPS. NO enhances LPS-induced p38 MAPK and TNF-α expression a In the study the NO eNOS enhances LPS-stimulated TNF-α expression in neonatal mouse cardiomyocytes. Activation of p38 MAPK is essential in LPS-stimulated TNF-α expression. Moreover, the effects of NO on LPS-stimulated TNF-α expression are mediated through p38 MAPK These to LPS of TNF-α in cardiomyocytes. The of the NO enhances LPS-induced TNF-α expression in cardiomyocytes in is levels of TNF-α to effects on TNF-α is to K.J. Cerami A. Annu. Rev. Cell Biol. 1993; 9: 317-343Google is expression of TNF-α by eNOS to of response in the in the of and to the of the the are TNF-α expression to expression Biol. and eNOS of TNF-α production the of the MAPK pathway in

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