Sustained augmentation of cardiac α 1A-adrenergic drive results in pathological remodeling with contractile dysfunction, progressive fibrosis and reactivation of matricellular protein genes

H. Chaulet; F. Lin; J Guo; W.A. Owens; J. Michalicek; S.H. Kesteven; Z. Guan; O.W. Prall; B.M. Mearns; M.P. Feneley; S.F. Steinberg; R.M. Graham

doi:10.1016/j.yjmcc.2006.01.015

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Sustained augmentation of cardiac α 1A-adrenergic drive results in pathological remodeling with contractile dysfunction, progressive fibrosis and reactivation of matricellular protein genes

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Sustained augmentation of cardiac α 1A-adrenergic drive results in pathological remodeling with contractile dysfunction, progressive fibrosis and reactivation of matricellular protein genes

H. Chaulet, F. Lin, J Guo, W.A. Owens, J. Michalicek, S.H. Kesteven, Z. Guan, O.W. Prall, B.M. Mearns, M.P. Feneley, …

Journal of molecular and cellular cardiology, Vol.40(4), pp.540-552

2006

DOI: 10.1016/j.yjmcc.2006.01.015

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Abstract

We previously reported that transgenic (TG) mice with cardiac-restricted α 1A-adrenergic receptor (α 1A-AR)-overexpression showed enhanced contractility, but no hypertrophy. Since chronic inotropic enhancement may be deleterious, we investigated if long-term, cardiac function and longevity are compromised. α 1A-TG mice, but not their non-TG littermates (NTLs), showed progressive loss of left ventricular (LV) hypercontractility (dP/dt max: 14,567 ± 603 to 11,610 ± 915 mmHg/s, P < 0.05, A1A1 line: 170-fold overexpression; and 13,625 ± 826 to 8322 ± 682 mmHg/s, respectively, P < 0.05, A1A4 line: 112-fold overexpression, at 2 and 6 months, respectively). Both TG lines developed LV fibrosis, but not LV dilatation or hypertrophy, despite activation of hypertrophic signaling pathways. Microarray and real time RT-PCR analyses revealed activation of matricellular protein genes, including those for thrombospondin 1, connective tissue growth factor and tenascin C, but not transforming growth factor β1. Life-span was markedly shortened (mean age at death: 155 days, A1A1 line; 224 days, A1A4 line compared with NTLs: > 300 days). Telemetric electrocardiography revealed that death in the α 1A-AR TG mice was due to cardiac standstill preceded by a progressive diminution in QRS amplitude, but not by arrhythmias. The QRS changes and sudden death could be mimicked by α 1-AR activation, and reversed preterminally by α 1-AR blockade, suggesting a relationship to stress- or activity-associated catecholamine release. Thus, long-term augmentation of cardiac α 1A-adrenergic drive leads to premature death and progressive LV fibrosis with reactivation of matricellular protein genes. To our knowledge this is the first evidence in vivo for a role of the α 1A-AR in ventricular fibrosis and in pathological cardiac remodeling.

Fibrosis

Matricellular

QRS amplitude

α 1A-Adrenergic receptor

Details

Title: Subtitle: Sustained augmentation of cardiac α 1A-adrenergic drive results in pathological remodeling with contractile dysfunction, progressive fibrosis and reactivation of matricellular protein genes
Creators: H. Chaulet - Victor Chang Cardiac Research Institute
F. Lin - UNSW Sydney
J Guo - Columbia University
W.A. Owens - UNSW Sydney
J. Michalicek - UNSW Sydney
S.H. Kesteven - UNSW Sydney
Z. Guan - UNSW Sydney
O.W. Prall - UNSW Sydney
B.M. Mearns - UNSW Sydney
M.P. Feneley - UNSW Sydney
S.F. Steinberg - Columbia University
R.M. Graham - UNSW Sydney
Resource Type: Journal article
Publication Details: Journal of molecular and cellular cardiology, Vol.40(4), pp.540-552
DOI: 10.1016/j.yjmcc.2006.01.015
ISSN: 0022-2828
eISSN: 1095-8584
Publisher: Elsevier Ltd
Language: English
Date published: 2006
Academic Unit: Anatomy and Cell Biology; Craniofacial Anomalies Research Center
Record Identifier: 9984284454402771

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