title: Dysfunction of the cholinergic anti-inflammatory pathway mediates organ damage in hypertension.
abstract: Inflammatory responses are associated with the genesis and progression of end-organ damage (EOD) in hypertension. A role for the α7 nicotinic acetylcholine receptor (α7nAChR) in inflammation has recently been identified. We tested the hypothesis that α7nAChR dysfunction contributes to hypertensive EOD. In both spontaneously hypertensive rats (SHRs) and rats with abdominal aorta coarctation-induced hypertension, atropine-induced tachycardia was blunted compared with normotensive controls. Both models of hypertension were associated with deficits in expression of the vesicular acetylcholine transporter and the α7nAChR in cardiovascular tissues. In hypertension induced by abdominal aorta coarctation, deficits in aortic vesicular acetylcholine transporter and α7nAChR were present both above and below the coarctation site, indicating that they were independent of the level of arterial pressure itself. Hypertension in 40-week-old SHRs was associated with cardiac and aortic hypertrophy. Morphological abnormalities consistent with EOD, along with elevated tissue levels of proinflammatory cytokines (tumor necrosis factor-α, interleukin-1β, and interleukin-6) were observed in the heart, kidney, and aorta. Chronic treatment of SHRs with the α7nAChR agonist PNU-282987 relieved EOD and inhibited tissue levels of proinflammatory cytokines and activation of nuclear factor κB. Greater serum levels of proinflammatory cytokines and more severe damage in the heart, aorta, and kidney were seen in α7nAChR(-/-) mice subjected to 2-kidney-1-clip surgery than in wild-type mice. A deficit in the cholinergic anti-inflammatory pathway appears to contribute to the pathogenesis of EOD in models of hypertension of varying etiology. This pathway may provide a new target for preventing cardiovascular disease resulting from hypertension.
authors.affiliation: Department of Pharmacology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Dong-Jie
authors.initials: DJ
authors.lastname: Li
authors.forename: Roger G
authors.initials: RG
authors.lastname: Evans
authors.forename: Zhong-Wei
authors.initials: ZW
authors.lastname: Yang
authors.forename: Shu-Wei
authors.initials: SW
authors.lastname: Song
authors.forename: Pei
authors.initials: P
authors.lastname: Wang
authors.forename: Xiu-Juan
authors.initials: XJ
authors.lastname: Ma
authors.forename: Chong
authors.initials: C
authors.lastname: Liu
authors.forename: Tao
authors.initials: T
authors.lastname: Xi
authors.forename: Ding-Feng
authors.initials: DF
authors.lastname: Su
authors.forename: Fu-Ming
authors.initials: FM
authors.lastname: Shen
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D001285:Atropine / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D006978:Hypertension, Renovascular / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology*; D018836:Inflammation Mediators / Q000097:blood / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009102:Multiple Organ Failure / Q000097:blood / Q000378:metabolism / Q000503:physiopathology*; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D050494:Vesicular Acetylcholine Transport Proteins / Q000235:genetics / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D001549:Benzamides; D001643:Bridged Bicyclo Compounds; C579166:Chrna7 protein, mouse; C579165:Chrna7 protein, rat; D018836:Inflammation Mediators; D018727:Muscarinic Antagonists; D016328:NF-kappa B; C498513:PNU-282987; D011978:Receptors, Nicotinic; C493460:Slc18a3 protein, mouse; D050494:Vesicular Acetylcholine Transport Proteins; D064569:alpha7 Nicotinic Acetylcholine Receptor; D001285:Atropine