title: Chronic knockdown of the nucleus of the solitary tract AT1 receptors increases blood inflammatory-endothelial progenitor cell ratio and exacerbates hypertension in the spontaneously hypertensive rat.
abstract: AT1 receptor subtype a (AT1Ra) expression is increased in the nucleus of the solitary tract (NTS) in spontaneously hypertensive rat (SHR) compared with Wistar Kyoto controls. However, the chronic role of AT1Ra in the NTS for cardiovascular control is not well understood. In this study, we investigated the hypothesis that the NTS AT1Ra is involved in the neural regulation of the peripheral inflammatory status and linked with hypertension. Transduction of brain neuronal cultures with recombinant adeno-associated virus type 2 (AAV2)-AT1R-small hairpin RNA (shRNA) resulted in a 72% decrease in AT1Ra mRNA and attenuated angiotensin II-induced increase in extracellular signal-regulated kinase 1/2 phosphorylation and neuronal firing. Specific NTS microinjection of AAV2-AT1R-shRNA vector in the SHR resulted in a ≈30 mm Hg increase in the mean arterial pressure compared with control vector-injected animals (Sc-shRNA: 154±4 mm Hg; AT1R-shRNA: 183±10 mm Hg) and induced a resetting of the baroreflex control of heart rate to higher mean arterial pressure. In addition, AAV2-AT1R-shRNA-treated SHRs exhibited a 74% decrease in circulating endothelial progenitor cells (CD90+, CD4- / CD5- / CD8-) and a 300% increase in the circulating inflammatory cells, including CD4+ + CD8+, CD45+ / 3+ T lymphocytes, and macrophages (CD68+). As a result, the endothelial progenitor cell/inflammatory cells ratio was decreased by 8- to 15-fold in the AT1R-shRNA-treated SHR. However, identical injection of AAV2-AT1R-shRNA into the NTS of Wistar Kyoto rats had no effect on mean arterial pressure and inflammatory cells. These observations suggest that increased expression of the AT1Ra in SHR NTS may present a counterhypertensive mechanism involving inflammatory/angiogenic cells.
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Shan
authors.forename: Jasenka
authors.initials: J
authors.lastname: Zubcevic
authors.forename: Peng
authors.initials: P
authors.lastname: Shi
authors.forename: Joo Y
authors.initials: JY
authors.lastname: Jun
authors.forename: Ying
authors.initials: Y
authors.lastname: Dong
authors.forename: Tatiane M
authors.initials: TM
authors.lastname: Murça
authors.forename: Gwyneth J
authors.initials: GJ
authors.lastname: Lamont
authors.forename: Adolfo
authors.initials: A
authors.lastname: Cuadra
authors.forename: Wei
authors.initials: W
authors.lastname: Yuan
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Qi
authors.forename: Qiuhong
authors.initials: Q
authors.lastname: Li
authors.forename: Julian F R
authors.initials: JF
authors.lastname: Paton
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Katovich
authors.forename: Colin
authors.initials: C
authors.lastname: Sumners
authors.forename: Mohan K
authors.initials: MK
authors.lastname: Raizada
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D002478:Cells, Cultured; D018450:Disease Progression; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques / Q000379:methods; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D007249:Inflammation / Q000097:blood / Q000235:genetics / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D060888:Real-Time Polymerase Chain Reaction; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis / Q000235:genetics*; D017552:Solitary Nucleus / Q000378:metabolism* / Q000473:pathology; D013234:Stem Cells / Q000166:cytology*
chemical_list: D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1
keywords: AT1R; NTS; baroreflex; endothelial progenitor cells; hypertension; inflammation
references.citation: Exp Neurol. 1990 Feb;107(2):164-9
references.pmid: 2303124
references.citation: Hypertension. 2007 Jun;49(6):1321-7
references.pmid: 17420334
references.citation: Hypertension. 2012 Nov;60(5):1316-23
references.pmid: 23045460
references.citation: Hypertension. 2011 Jun;57(6):1026-33
references.pmid: 21536990
references.citation: J Neurochem. 1993 May;60(5):1949-52
references.pmid: 8473909
references.citation: Hypertension. 2012 Apr;59(4):755-62
references.pmid: 22331383
references.citation: Am J Physiol. 1998 Nov;275(5):R1611-9
references.pmid: 9791081
references.citation: Curr Hypertens Rep. 2007 Jun;9(3):242-7
references.pmid: 17519132
references.citation: J Exp Med. 2009 Dec 21;206(13):2897-906
references.pmid: 19934019
references.citation: Hypertension. 2009 Jan;53(1):97-103
references.pmid: 19015400
references.citation: Hypertension. 1990 Feb;15(2 Suppl):I45-50
references.pmid: 2298476
references.citation: Clin Exp Pharmacol Physiol. 2010 Feb;37(2):e52-7
references.pmid: 19566837
references.citation: Am J Physiol. 1997 Jul;273(1 Pt 2):R28-34
references.pmid: 9249529
references.citation: Circ Res. 2010 Oct 1;107(7):934-8
references.pmid: 20689062
references.citation: Nature. 2003 Jan 23;421(6921):384-8
references.pmid: 12508119
references.citation: Brain Res Bull. 2003 May 15;60(3):209-14
references.pmid: 12754082
references.citation: Am J Physiol. 1994 Jul;267(1 Pt 2):H259-66
references.pmid: 7914065
references.citation: Neuroscience. 2005;134(3):947-63
references.pmid: 15994021
references.citation: Circ Res. 2005 Feb 18;96(3):277-9
references.pmid: 15662030
references.citation: Brain Behav Immun. 2007 Aug;21(6):736-45
references.pmid: 17467231
references.citation: J Physiol. 1999 Nov 15;521 Pt 1:213-25
references.pmid: 10562346
references.citation: Brain Res. 1986 Feb 5;364(2):233-40
references.pmid: 3947969
references.citation: Cardiovasc Res. 2009 Jun 1;82(3):503-12
references.pmid: 19246475
references.citation: Am J Physiol Heart Circ Physiol. 2005 Oct;289(4):H1683-91
references.pmid: 15908469
references.citation: Nat Rev Neurosci. 2006 May;7(5):335-46
references.pmid: 16760914
references.citation: Front Physiol. 2012 May 07;3:128
references.pmid: 22586409
references.citation: Hypertension. 2013 Mar;61(3):622-7
references.pmid: 23319541