(Circulation. 1995;92:918-925.)
© 1995 American Heart Association, Inc.
Articles |
Chronic Hypoxia Differentially Regulates 
1-Adrenergic Receptor Subtype mRNAs and Inhibits 1-Adrenergic Receptor–Stimulated Cardiac Hypertrophy and Signaling
From the Cardiology Section, Veterans Affairs Medical Center, the Cardiovascular Research Institute and the Department of Medicine, University of California, San Francisco.
Correspondence to Joel S. Karliner, MD, Cardiology Section (111C), Veterans Affairs Medical Center, 4150 Clement St, San Francisco, CA 94121.
Background After myocardial ischemia and/or
infarction, surviving cardiac myocytes in and around the injured zone
develop hypertrophy to compensate for the loss of
contractile units due to myocyte injury and death. One of the factors
that may be involved in the development of hypertrophy
after ischemic injury is norepinephrine (NE), an
agent that induces hypertrophy of cardiac myocytes through
the 
1-adrenergic receptor (AR). It is not known,
however, whether hypoxia, a major component of
ischemia, has any direct effect on NE-stimulated
hypertrophy. Therefore, we sought to determine whether
chronic hypoxia could alter NE-stimulated
hypertrophy and if so, whether this alteration was related
to 1-AR–mediated signaling and 1-AR
changes at both the protein and mRNA levels.
Methods and Results We developed a model of chronic
hypoxia in cultured neonatal rat cardiac myocytes in which
myocytes were exposed to 1% oxygen for 72 hours. Initially, we
observed that chronic hypoxia inhibited NE-stimulated
hypertrophy, as reflected by decreases in both new protein
synthesis and total protein content during chronic hypoxia.
Then we found that chronic hypoxia also inhibited
1-AR–transduced phosphatidylinositol hydrolysis, as
indicated by a reduction in 1-AR–stimulated inositol
phosphate production in hypoxic cells. These observations
suggested that the inhibition of NE-stimulated hypertrophy
seen during chronic hypoxia was due to impairment of
1-AR–mediated signaling and could result from changes
in 1-AR numbers and/or subtype distribution. To address
this issue, we determined 1-AR density and subtype
distribution by radioligand binding and 1-AR
subtype mRNAs, including 1A/D-, 1B-, and
1C-ARs, by RNase protection assays. We found that
chronic hypoxia differentially regulated both the
pharmacologically defined 1-AR subtypes and the mRNAs
for the 1-AR subtypes. Thus, hypoxia for 72
hours coordinately downregulated both the pharmacologically defined
1A-AR density and the 1C-AR mRNA level.
During normoxia, NE increased the pharmacologically defined
1A-AR density and the 1C-AR mRNA level,
but hypoxia for 72 hours prevented these NE-mediated
changes.
Conclusions Chronic hypoxia (1) inhibits
1-AR–mediated hypertrophy of cardiac
myocytes and 1-AR–transduced phosphatidylinositol
hydrolysis and (2) downregulates both the pharmacologically defined
1A-AR density and the 1C-AR mRNA
level.
Key Words: receptors, adrenergic, alpha • hypoxia • hypertrophy • myocytes
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