标题：Low- and high-level transgenic expression of β2-adrenergic receptors differentially affect cardiac hypertrophy and function in Gαq-overexpressing mice
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：1999
卷号：96
期号：11
页码：6400-6405
DOI：10.1073/pnas.96.11.6400
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Transgenic overexpression of Gq in the heart triggers events leading to a phenotype of eccentric hypertrophy, depressed ventricular function, marked expression of hypertrophy-associated genes, and depressed {beta}-adrenergic receptor ({beta}AR) function. The role of {beta}AR dysfunction in the development of this failure phenotype was delineated by transgenic coexpression of the carboxyl terminus of the {beta}AR kinase ({beta}ARK), which acts to inhibit the kinase, or concomitant overexpression of the {beta}2AR at low ({approx}30-fold, Gq/{beta}2ARL), moderate ({approx}140-fold, Gq/{beta}2ARM), and high ({approx}1,000-fold, Gq/{beta}2ARH) levels above background {beta}AR density. Expression of the {beta}ARK inhibitor had no effect on the phenotype, consistent with the lack of increased {beta}ARK levels in Gq mice. In marked contrast, Gq/{beta}2ARL mice displayed rescue of hypertrophy and resting ventricular function and decreased cardiac expression of atrial natriuretic factor and -skeletal actin mRNA. These effects occurred in the absence of any improvement in basal or agonist-stimulated adenylyl cyclase (AC) activities in crude cardiac membranes, although restoration of a compartmentalized {beta}2AR/AC signal cannot be excluded. Higher expression of receptors in Gq/{beta}2ARM mice resulted in salvage of AC activity, but hypertrophy, ventricular function, and expression of fetal genes were unaffected or worsened. With {approx}1,000-fold overexpression, the majority of Gq/{beta}2ARH mice died with cardiomegaly at 5 weeks. Thus, although it appears that excessive, uncontrolled, or generalized augmentation of {beta}AR signaling is deleterious in heart failure, selective enhancement by overexpressing the {beta}2AR subtype to limited levels restores not only ventricular function but also reverses cardiac hypertrophy.
