title: Improving vagal activity ameliorates cardiac fibrosis induced by angiotensin II: in vivo and in vitro.
abstract: Cardiac remodeling is characterized by overactivity of the renin-angiotensin system (RAS) and withdrawal of vagal activity. We hypothesized that improving vagal activity could attenuate cardiac fibrosis induced by angiotensin II (Ang II) in vivo and in vitro. Rats were subjected to abdominal aorta constriction (AAC) with or without pyridostigmine (PYR) (31 mg/kg/d). After 8 weeks, PYR significantly decreased Ang II level, AT1 protein expression, and collagen deposition in cardiac tissue and improved heart rate variability, baroreflex sensitivity and cardiac function, which were abolished by atropine. In vitro, treatment of cardiac fibroblasts (CFs) with Ang II (10(-7) M) increased cell proliferation, migration, transformation, and secretory properties, which were significantly diminished by acetylcholine (ACh, 10(-6) M). Subsequently, Ang II significantly increased collagen type I expression as well as metalloproteinase (MMP)-2 expression and activity. Transforming growth factor (TGF)-β1 expression and Smad3 phosphorylation presented a similar trend. Notably, the knockdown of the acetylcholine M2 receptor by siRNA could abolish ACh anti-fibrotic action. These data implicated cholinesterase inhibitor can increase vagal activity and reduce local Ang II level, and ACh inhibit Ang II pro-fibrotic effects. Our findings suggested that the parasympathetic nervous system can serve as a promising target for cardiac remodeling treatment.
authors.affiliation: Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, P. R. China.
authors.forename: Jin-Jun
authors.initials: JJ
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, P. R. China.
authors.forename: Ning
authors.initials: N
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, P. R. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, P. R. China.
authors.forename: Mei
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, P. R. China.
authors.forename: Xiao-Jiang
authors.initials: XJ
authors.lastname: Yu
authors.affiliation: Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, P. R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, P. R. China.
authors.forename: Yong-hua
authors.initials: YH
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, P. R. China.
authors.forename: Wei-Jin
authors.initials: WJ
authors.lastname: Zang
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D002800:Cholinesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D003094:Collagen / Q000096:biosynthesis; D003251:Constriction, Pathologic / Q000188:drug therapy; D004353:Drug Evaluation, Preclinical; D005347:Fibroblasts / Q000502:physiology; D005355:Fibrosis; D055785:Gene Knockdown Techniques; D006331:Heart Diseases / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D011729:Pyridostigmine Bromide / Q000494:pharmacology* / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D043585:Receptor, Muscarinic M2 / Q000235:genetics / Q000378:metabolism; D014630:Vagus Nerve / Q000187:drug effects / Q000503:physiopathology*
chemical_list: D002800:Cholinesterase Inhibitors; D043585:Receptor, Muscarinic M2; D000804:Angiotensin II; D003094:Collagen; D011729:Pyridostigmine Bromide