title: Chronic carvedilol treatment partially reverses the right ventricular failure transcriptional profile in experimental pulmonary hypertension.
abstract: Right ventricular failure (RVF) is the most frequent cause of death in patients with pulmonary arterial hypertension (PAH); however, specific therapies targeted to treat RVF have not been developed. Chronic treatment with carvedilol has been shown to reduce established maladaptive right ventricle (RV) hypertrophy and to improve RV function in experimental PAH. However, the mechanisms by which carvedilol improves RVF are unknown. We have previously demonstrated by microarray analysis that RVF is characterized by a distinct gene expression profile when compared with functional, compensatory hypertrophy. We next sought to identify the effects of carvedilol on gene expression on a genome-wide basis. PAH and RVF were induced in male Sprague-Dawley rats by the combination of VEGF-receptor blockade and chronic hypoxia. After RVF was established, rats were treated with carvedilol or vehicle for 4 wk. RNA was isolated from RV tissue and hybridized for microarray analysis. An initial prediction analysis of carvedilol-treated RVs showed that the gene expression profile resembled the RVF prediction set. However, a more extensive analysis revealed a small group of genes differentially expressed after carvedilol treatment. Further analysis categorized these genes in pathways involved in cardiac hypertrophy, mitochondrial dysfunction, and protein ubiquitination. Genes encoding proteins in the cardiac hypertrophy and protein ubiquitination pathways were downregulated in the RV by carvedilol, while genes encoding proteins in the mitochondrial dysfunction pathway were upregulated by carvedilol. These gene expression changes may explain some of the mechanisms that underlie the functional improvement of the RV after carvedilol treatment.
authors: Victoria Johnson Center for Lung Obstructive Disease Research, Virginia Commonwealth University, Richmond, Virginia, USA.
authors: Jennifer I
authors: JI
authors: Drake
authors: Jose
authors: J
authors: Gomez-Arroyo
authors: Catherine I
authors: CI
authors: Dumur
authors: Donatas
authors: D
authors: Kraskauskas
authors: Ramesh
authors: R
authors: Natarajan
authors: Harm J
authors: HJ
authors: Bogaard
authors: Paul
authors: P
authors: Fawcett
authors: Norbert F
authors: NF
authors: Voelkel
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D006332:Cardiomegaly / Q000150:complications / Q000235:genetics; D000077261:Carvedilol; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000150:complications* / Q000235:genetics; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D011412:Propanolamines / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D054875:Ubiquitination / Q000187:drug effects / Q000235:genetics; D018497:Ventricular Dysfunction, Right / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics*
chemical_list: D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol
keywords: microarray; right ventricle; right ventricular failure
references: Nucleic Acids Res. 2003 Jan 1;31(1):334-41
references: 12520017
references: Basic Res Cardiol. 2011 Nov;106(6):1269-81
references: 22057716
references: BMC Bioinformatics. 2003 Aug 20;4:32
references: 12930545
references: Bioinformatics. 2004 Nov 22;20(17):3246-8
references: 15180930
references: Circulation. 2012 Oct 2;126(14):1705-16
references: 22932257
references: Circ Res. 2007 Mar 30;100(6):923-9
references: 17332430
references: J Biol Chem. 2012 Feb 24;287(9):6139-49
references: 22219185
references: J Nutr. 2004 Apr;134(4):771-5
references: 15051824
references: Circulation. 2010 Jan 19;121(2):252-8
references: 20048206
references: Proc Natl Acad Sci U S A. 2002 Aug 20;99(17):11205-10
references: 12163646
references: J Mol Cell Cardiol. 2008 Jun;44(6):992-1001
references: 18377926
references: J Natl Cancer Inst. 2003 Jan 1;95(1):14-8
references: 12509396
references: Circ Heart Fail. 2013 Jan;6(1):136-44
references: 23152488
references: Nucleic Acids Res. 2002 Jan 1;30(1):207-10
references: 11752295
references: Stroke. 2005 Jul;36(7):1533-7
references: 15947259
references: Am J Respir Cell Mol Biol. 2011 Dec;45(6):1239-47
references: 21719795
references: J Mol Cell Cardiol. 2012 Mar;52(3):526-37
references: 22085703
references: J Am Coll Cardiol. 2001 Jan;37(1):183-8
references: 11153735
references: J Am Coll Cardiol. 2002 May 1;39(9):1450-5
references: 11985906
references: J Mol Med (Berl). 1998 Oct;76(11):725-46
references: 9826118
references: Neoplasia. 2012 Jul;14(7):559-71
references: 22904674
references: Am J Respir Cell Mol Biol. 2012 Nov;47(5):698-708
references: 22842494
references: J Clin Invest. 2007 Sep;117(9):2445-58
references: 17786238
references: Circulation. 2009 Nov 17;120(20):1951-60
references: 19884466
references: J Pharmacol Exp Ther. 1996 Apr;277(1):128-36
references: 8613909
references: Heart Fail Clin. 2012 Oct;8(4):633-41
references: 22999245
references: J Cell Sci. 2002 Jan 1;115(Pt 1):175-83
references: 11801735
references: Am J Respir Crit Care Med. 2010 Sep 1;182(5):652-60
references: 20508210
references: Cardiovasc Res. 2010 Jan 15;85(2):357-66
references: 19850579
references: J Clin Invest. 2006 Mar;116(3):615-22
references: 16511594
references: Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14863-8
references: 9843981
references: J Comput Biol. 2002;9(3):505-11
references: 12162889
references: Eur Heart J. 2010 Sep;31(18):2291-300
references: 20601390
references: Nucleic Acids Res. 2007 Jan;35(Database issue):D247-52
references: 17130144
references: Cancer Inform. 2007 Feb 04;3:11-7
references: 19455231
references: J Thorac Cardiovasc Surg. 2009 Apr;137(4):853-61
references: 19327508
references: Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5116-21
references: 11309499
references: Biochim Biophys Acta. 2013 Jan;1831(1):203-12
references: 22735359
references: Cardiovasc Res. 2008 Aug 1;79(3):472-80
references: 18375498
references: Mol Cell Biol. 2012 Oct;32(19):4025-34
references: 22851699
references: Eur Respir Rev. 2011 Dec;20(122):243-53
references: 22130817
references: Am J Physiol Lung Cell Mol Physiol. 2012 Feb 15;302(4):L363-9
references: 21964406
references: Acta Biochim Biophys Sin (Shanghai). 2010 Apr;42(4):253-8
references: 20383463
references: Genome Res. 2003 Sep;13(9):2129-41
references: 12952881
references: Eur Respir J. 2012 Dec;40(6):1555-65
references: 22743666
references: Compr Physiol. 2011 Jan;1(1):525-40
references: 23737184
references: J Pharmacol Exp Ther. 1992 Oct;263(1):92-8
references: 1357162
references: Ann Am Thorac Soc. 2013 Feb;10(1):1-9
references: 23509326