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

Chaulet, H. and Lin, F. and Guo, J. and Owens, W. A. and Michalicek, J. and Kesteven, S. H. and Guan, Z. and Prall, O. W. and Mearns, B. M. and Feneley, M. P. and Steinberg, S. F. and Graham, R. M. (2006) 'Sustained augmentation of cardiac 1A-adrenergic drive results in pathological remodeling with contractile dysfunction, progressive fibrosis and reactivation of matricellular protein genes.', Journal of molecular and cellular cardiology., 40 (4). pp. 540-552.

Abstract

We previously reported that transgenic (TG) mice with cardiac-restricted α1A-adrenergic receptor (α1A-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. α1A-TG mice, but not their non-TG littermates (NTLs), showed progressive loss of left ventricular (LV) hypercontractility (dP/dtmax: 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 α1A-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 α1-AR activation, and reversed preterminally by α1-AR blockade, suggesting a relationship to stress- or activity-associated catecholamine release. Thus, long-term augmentation of cardiac α1A-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 α1A-AR in ventricular fibrosis and in pathological cardiac remodeling.

Item Type:Article
Keywords:Adrenergic receptor, Fibrosis, Matricellular, QRS amplitude.
Full text:Full text not available from this repository.
Publisher Web site:http://dx.doi.org/10.1016/j.yjmcc.2006.01.015
Record Created:11 Feb 2009
Last Modified:09 Apr 2010 16:41

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