Mr. Bristow et al., REDUCED BETA(1) RECEPTOR MESSENGER-RNA ABUNDANCE IN THE FAILING HUMANHEART, The Journal of clinical investigation, 92(6), 1993, pp. 2737-2745
Heart failure in humans is characterized by alterations in myocardial
adrenergic signal transduction, the most prominent of which is down-re
gulation of beta1-adrenergic receptors. We tested the hypothesis that
down-regulation of beta1-adrenergic receptors in the failing human hea
rt is related to decreased steady-state levels of beta1 receptor mRNA.
Due to the extremely low abundance of beta1 receptor mRNA, measuremen
ts were possible only by quantitative polymerase chain reaction (QPCR)
or by RNase protection methods. Because the beta1 receptor gene is in
tronless and beta1 receptor mRNA abundance is low, QPCR yielded genomi
c amplification in total RNA, and mRNA measurements had to be performe
d in poly(A)+-enriched RNA. By QPCR the concentration of beta1 recepto
r mRNA varied from 0.34 to 7.8 x 10(7) molecules/mug poly(A)+-enriched
RNA, and the assay was sensitive to 16.7 zeptomol. Using 100-mg aliqu
ots of left ventricular myocardium obtained from organ donors (nonfail
ing ventricles, n = 12) or heart transplant recipients (failing ventri
cles, n = 13), the respective beta1 mRNA levels measured by QPCR were
4.2+/-0.7 x 10(7)/mug vs. 2.10+/-0.3 X 10(7)/mug (p = 0.006). In these
same nonfailing and failing left ventricles the respective beta1-adre
nergic receptor densities were 67.9+/-6.9 fmol/mg vs. 29.6+/-3.5 fmol/
mg (P = 0.0001 ). Decreased mRNA abundance in the failing ventricles w
as confirmed by RNase protection assays in total RNA, which also demon
strated a 50% reduction in beta1 message abundance. We conclude that d
own-regulation of beta1 receptor mRNA contributes to down-regulation o
f beta1 adrenergic receptors in the failing human heart.