© 1999 American Heart Association, Inc.
Original Contribution |
Apoptosis of Cardiac Myocytes in Gs
Transgenic Mice
From the Cardiovascular and Pulmonary Research Institute (Y-J.G., Y.I., D.E.V., S.F.V.), Allegheny University of the Health Sciences, Pittsburgh, Pa; Departments of Molecular and Cellular Biology and Oncology Research (T.E.W.), The Greenville Hospital System, Greenville, SC; Department of Microbiology and Molecular Medicine (T.E.W.), Clemson University, Clemson, SC; Department of Pathology (S.P.B.), University of Alabama at Birmingham; and COR Therapeutics, Inc (C.J.H.), South San Francisco, Calif.
Correspondence to Stephen F. Vatner, MD, George J. Magovern Professor and Director, Cardiovascular Research Institute, Allegheny University of Health Sciences, 320 East North Avenue, Pittsburgh, PA 15212.
Abstract—The stimulatory
GTP-binding protein Gs
transmits signals from
catecholamine receptors to activate adenylyl
cyclase and thereby initiate a cascade leading to cardiac chronotropy
and inotropy. Transgenic mice overexpressing the Gs subunit (Gs)
selectively in their hearts exhibit increased cardiac
contractility in response to ß-adrenergic receptor
stimulation. However, with aging, these mice develop a
cardiomyopathy. This study sought morphological and
biochemical evidence that overexpression of Gs is associated with
increased myocyte apoptosis in the older animals and to
determine whether such overexpression can promote apoptosis of
isolated neonatal cardiac myocytes exposed to ß-adrenergic receptor
agonists. In the hearts of 15- to 18-month-old Gs transgenic mice,
histochemistry and electron microscopy illustrated the existence of
numerous myocytes with abnormal nuclei embedded in collagen-rich
connective tissue. Terminal deoxyribonucleotide
transferase-mediated dUTP nick-end labeling (TUNEL, for in situ
labeling of DNA breaks) demonstrated that 
0.6% of myocyte
nuclei contained fragmented DNA. Agarose gel electrophoresis provided
further biochemical evidence of apoptosis by showing
internucleosomal DNA fragmentation. Cultured cardiac myocytes from
newborn Gs transgenic mice showed increased TUNEL staining and
internucleosomal DNA fragmentation compared with wild-type controls
when treated with the ß-agonist isoproterenol. Thus, enhanced
activation of ß-adrenergic signaling by overexpression of Gs in
the hearts of transgenic mice induces apoptosis of cardiac
myocytes. This represents a potential mechanism that may
contribute to the development of cardiomyopathy in
this model.
Key Words: adenylyl cyclase • ß-adrenergic receptor • catecholamine • programmed cell death • cardiomyopathy
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