Sustained augmentation of cardiac alpha1A-adrenergic drive results in pathological remodeling with contractile dysfunction, progressive fibrosis and reactivation of matricellular protein genes.
We previously reported that transgenic (TG) mice with cardiac-restricted alpha(1A)-adrenergic receptor (alpha(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. alpha(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 beta1. 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 alpha(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 alpha(1)-AR activation, and reversed preterminally by alpha(1)-AR blockade, suggesting a relationship to stress- or activity-associated catecholamine release. Thus, long-term augmentation of cardiac alpha(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 alpha(1A)-AR in ventricular fibrosis and in pathological cardiac remodeling.
Chaulet
H
H
Victor Chang Cardiac Research Institute and St. Vincent's Hospital, Darlinghurst, New South Wales 2010, Australia.
Lin
F
F
Guo
J
J
Owens
W A
WA
Michalicek
J
J
Kesteven
S H
SH
Guan
Z
Z
Prall
O W
OW
Mearns
B M
BM
Feneley
M P
MP
Steinberg
S F
SF
Graham
R M
RM
D000818:Animals; D004719:Endomyocardial Fibrosis / Q000235:genetics* / Q000473:pathology; D015870:Gene Expression / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000235:genetics*; D051379:Mice; D009200:Myocardial Contraction / Q000235:genetics*; D009206:Myocardium / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D018340:Receptors, Adrenergic, alpha-1 / Q000096:biosynthesis / Q000235:genetics*; D020257:Ventricular Remodeling / Q000235:genetics*
D018340:Receptors, Adrenergic, alpha-1