title: The Nox1/4 Dual Inhibitor GKT137831 or Nox4 Knockdown Inhibits Angiotensin-II-Induced Adult Mouse Cardiac Fibroblast Proliferation and Migration. AT1 Physically Associates With Nox4.
abstract: Both oxidative stress and inflammation contribute to chronic hypertension-induced myocardial fibrosis and adverse cardiac remodeling. Here we investigated whether angiotensin (Ang)-II-induced fibroblast proliferation and migration are NADPH oxidase (Nox) 4/ROS and IL-18 dependent. Our results show that the potent induction of mouse cardiac fibroblast (CF) proliferation and migration by Ang-II is markedly attenuated by Nox4 knockdown and the Nox inhibitor DPI. Further, Nox4 knockdown and DPI pre-treatment attenuated Ang-II-induced IL-18, IL-18Rα and collagen expression, and MMP9 and LOX activation. While neutralization of IL-18 blunted Ang-II-induced CF proliferation and migration, knockdown of MMP9 attenuated CF migration. The antioxidant NAC and the cell-permeable SOD mimetics Tempol, MnTBAP, and MnTMPyP attenuated oxidative stress and inhibited CF proliferation and migration. The Nox1/Nox4 dual inhibitor GKT137831 also blunted Ang-II-induced H2 O2 production and CF proliferation and migration. Further, AT1 bound Nox4, and Ang-II enhanced their physical association. Notably, GKT137831 attenuated the AT1/Nox4 interaction. These results indicate that Ang-II induces CF proliferation and migration in part via Nox4/ROS-dependent IL-18 induction and MMP9 activation, and may involve AT1/Nox4 physical association. Thus, either (i) neutralizing IL-18, (ii) blocking AT1/Nox4 interaction or (iii) use of the Nox1/Nox4 inhibitor GKT137831 may have therapeutic potential in chronic hypertension-induced adverse cardiac remodeling.
authors.affiliation: Microbiology, Tulane University School of Medicine, New Orleans, Louisiana.
authors.forename: Naveen K
authors.initials: NK
authors.lastname: Somanna
authors.affiliation: Medicine, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Valente
authors.affiliation: Department of Medical Pharmacology and Physiology, University of Missouri-Columbia, Columbia, Missouri.
authors.forename: Maike
authors.initials: M
authors.lastname: Krenz
authors.affiliation: Medicine/Cardiology, University of Missouri, Columbia, Missouri.
authors.forename: William P
authors.initials: WP
authors.lastname: Fay
authors.affiliation: Medicine/Cardiology, University of Missouri, Columbia, Missouri.
authors.forename: Patrice
authors.initials: P
authors.lastname: Delafontaine
authors.affiliation: Medicine/Cardiology, University of Missouri, Columbia, Missouri.|Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri.
authors.forename: Bysani
authors.initials: B
authors.lastname: Chandrasekar
mesh_terms: D000375:Aging; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology*; D055785:Gene Knockdown Techniques; D006801:Humans; D020382:Interleukin-18 / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000166:cytology*; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology*; D047069:Pyrazolones; D011725:Pyridines / Q000494:pharmacology*; D011728:Pyridones; D017382:Reactive Oxygen Species / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D020382:Interleukin-18; D016328:NF-kappa B; D011720:Pyrazoles; D047069:Pyrazolones; D011725:Pyridines; D011728:Pyridones; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D018808:Transcription Factor AP-1; D000804:Angiotensin II; C576694:setanaxib; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; D020780:Matrix Metalloproteinase 9