Myocardial-directed overexpression of the human beta(1)-adrenergic receptor in transgenic mice.
The beta(1)-adrenergic receptor (AR) is the dominant subtype in non-failing and failing myocardium. beta(1)-AR signaling, by the endogenous neurotransmitter norepinephrine, is central to the regulation of myocardial contractility. In heart failure, the beta(1)-AR undergoes subtype-selective downregulation which may protect against the increased cardiac adrenergic drive associated with this pathophysiological state. To examine the hypothesis that chronically increased beta(1)-AR mediated signaling has adverse myocardial effects, transgenic mice overexpressing the human beta(1)-AR in a cardiac-selective context were produced, utilizing an alpha-myosin heavy chain (MHC) promoter. In these mice, beta(1)-AR protein abundance was approximately 24-46-fold (1-2 pmol/mg protein) that of wild-type mice. Histopathological examination of young (4 months old) and old (approximately 9 months old) transgenic mouse hearts consistently demonstrated large areas of interstitial replacement fibrosis, marked myocyte hypertrophy and myofibrilar disarray. In addition, increased expression of the pre-apoptotic marker, Bax, was observed coincident with regions of fibrosis accompanied by an increased apoptotic index, as measured by TUNEL assay. Older non-transgenic mice exhibited a slight tendency towards a decreased fractional shortening, whereas older beta(1)-AR transgenic mice had a marked reduction in fractional shortening (%FS approximately 30) as determined by echocardiography. Additionally, older beta(1)-AR transgenic mice had an increased left ventricular chamber size. In summary, cardiac-directed overexpression of the human beta(1)-AR in transgenic mice leads to a significant histopathological phenotype with no apparent functional consequence in younger mice and a variable degree of cardiac dysfunction in older animals. This model system may ultimately prove useful for investigating the biological basis of adrenergically-mediated myocardial damage in humans.
Bisognano
J D
JD
Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado, 80262, USA.
Weinberger
H D
HD
Bohlmeyer
T J
TJ
Pende
A
A
Raynolds
M V
MV
Sastravaha
A
A
Roden
R
R
Asano
K
K
Blaxall
B C
BC
Wu
S C
SC
Communal
C
C
Singh
K
K
Colucci
W
W
Bristow
M R
MR
Port
D J
DJ
D000818:Animals; D017209:Apoptosis; D015415:Biomarkers; D004452:Echocardiography / Q000379:methods; D015870:Gene Expression; D006321:Heart / Q000503:physiopathology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2; D018342:Receptors, Adrenergic, beta-1 / Q000096:biosynthesis / Q000235:genetics*; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; C494827:Bax protein, mouse; D015415:Biomarkers; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018342:Receptors, Adrenergic, beta-1; D051028:bcl-2-Associated X Protein