title: The TIR/BB-loop mimetic AS-1 prevents cardiac hypertrophy by inhibiting IL-1R-mediated MyD88-dependent signaling.
abstract: Activation of NF-κB contributes to cardiac hypertrophy and the interleukin-1 receptor (IL-1R)-mediated MyD88-dependent signaling pathway predominately activates NF-κB. Recent studies have shown that the TIR/BB-Loop mimetic (AS-1) disrupted the interaction of MyD88 with the IL-1R, resulting in blunting of NF-κB activation. We have examined the effects of AS-1 on the IL-1β-induced hypertrophic response using cultured neonatal cardiac myocytes in vitro and transverse aortic constriction (TAC) pressure overload-induced cardiac hypertrophy in vivo. Neonatal cardiac myocytes were treated with AS-1 15 min prior to IL-1β stimulation for 24 h. AS-1 treatment significantly attenuated IL-1β-induced hypertrophic responses of cardiac myocytes. In vivo experiments showed that AS-1 administration prevented cardiac hypertrophy and dysfunction induced by pressure overload. AS-1 administration disrupted the interaction of IL-1R with MyD88 in the pressure overloaded hearts and prevented activation of NF-κB. In addition, AS-1 prevented increases in activation of the MAPK pathway (p38 and p-ERK) in TAC-induced hypertrophic hearts. Our data suggest that the IL-1R-mediated MyD88-dependent signaling pathway plays a role in the development of cardiac hypertrophy and AS-1 attenuation of cardiac hypertrophy is mediated by blocking the interaction between IL-1R and MyD88, resulting in decreased NF-κB binding activity and decreased MAPK activation.
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, Jiangsu, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhu
authors.forename: Ting
authors.initials: T
authors.lastname: Li
authors.forename: Juan
authors.initials: J
authors.lastname: Song
authors.forename: Chunyang
authors.initials: C
authors.lastname: Liu
authors.forename: Yulong
authors.initials: Y
authors.lastname: Hu
authors.forename: Lingli
authors.initials: L
authors.lastname: Que
authors.forename: Tuanzhu
authors.initials: T
authors.lastname: Ha
authors.forename: Jim
authors.initials: J
authors.lastname: Kelley
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.forename: Chuanfu
authors.initials: C
authors.lastname: Li
authors.forename: Yuehua
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D032701:Biomimetics; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D053583:Interleukin-1beta / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051193:Toll-Like Receptors / Q000378:metabolism*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D011759:Pyrrolidines; D017472:Receptors, Interleukin-1; D051193:Toll-Like Receptors; C475931:hydrocinnamoyl-1-valyl pyrrolidine; D048051:p38 Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D014633:Valine