Reduced Beta1 Receptor Messenger RNA Abundance in the Failing Human Heart

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Abstract

Heart failure in humans is characterized by alterations in myocardial adrenergic signal transduction, the most prominent of which is down-regulation of beta1-adrenergic receptors. We tested the hypothesis that down-regulation of beta1-adrenergic receptors in the failing human heart is related to decreased steady-state levels of beta1 receptor mRNA. Due to the extremely low abundance of beta1 receptor mRNA, measurements were possible only by quantitative polymerase chain reaction (QPCR) or by RNase protection methods. Because the beta1 receptor gene is intronless and beta1 receptor mRNA abundance is low, QPCR yielded genomic amplification in total RNA, and mRNA measurements had to be performed in poly(A)+\-enriched RNA. By QPCR the concentration of beta (1) receptor mRNA varied from 0.34 to 7.8 x 107 molecules/micrograms poly(A)+\-enriched RNA, and the assay was sensitive to 16.7 zeptomol. Using 100-mg aliquots of left ventricular myocardium obtained from organ donors (nonfailing ventricles, n = 12) or heart transplant recipients (failing ventricles, n = 13), the respective beta1 mRNA levels measured by QPCR were 4.2+/-0.7 x 107/micrograms vs. 2.10+/-0.3 x 107/micrograms (P = 0.006). In these same nonfailing and failing left ventricles the respective beta1-adrenergic 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 was confirmed by RNase protection assays in total RNA, which also demonstrated a 50% reduction in beta1 message abundance. We conclude that down-regulation of beta1 receptor mRNA contributes to down-regulation of beta1 adrenergic receptors in the failing human heart. (J. Clin. Invest. 1993. 92:2737-2745.) Key words: beta-adrenergic. heart failure. messenger RNA. polymerase chain reaction. receptor

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