Regional Distribution of β-Adrenoceptors in the Human Heart

Brodde, Otto‐Erich; Schüler, Stephan; Kretsch, Roland; Brinkmann, Matthias; Borst, H. G.; Hetzer, Roland; Reidemeister, J. Chr.; Warnecke, H.; Zerkowski, Hans‐Reinhard

doi:10.1097/00005344-198611000-00021

Cited by 171 publications

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“…In addition, the degree of myocyte hypertrophy was judged to be histologically and morphometrically similar in the two myocardial failure groups. The downregulation in ␤ 1 -adrenergic receptor protein and mRNA, considered to be a phenotypic marker of systolic dysfunction (25), and upregulation in ANP gene expression, a phenotypic marker of hypertrophy (26), were predicted from previous results in explanted human hearts (1,4,6,7,9,10,(27)(28)(29).…”

Section: Discussionmentioning

confidence: 83%

“…From regions of the two curves that collinearly amplify, it is then possible to determine the original amount of unknown mRNA, provided that a known amount of internal standard is added. The PCR products are identified by direct PCR sequencing, and several (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) internal standard cRNAs can be built into a single internal standard construct driven by the bacteriophage T 7 RNA polymerase promoter (1). When possible the amplified regions of transcripts of interest are selected to cross-splice junctions so amplification of genomic material does not contaminate the assay.…”

Section: Measurement Of Mrna Abundance By Reverse Transcription-quantmentioning

confidence: 99%

“…Previous studies in aliquots of explanted human ventricular myocardium, typically removed at the time of cardiac transplantation, have indicated that the failing heart exhibits changes in gene expression at the mRNA (1)(2)(3)(4)(5)(6)(7)(8) or protein gene product level (5)(6)(7)(8)(9)(10). However, one of the problems with using explanted hearts to investigate changes in gene expression is that failing tissue is only available from hearts with end-stage myocardial disease, in which numerous factors (e.g., multiple drug therapy) may obscure true pathogenic changes in gene expression.…”

Section: Introductionmentioning

confidence: 99%

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Changes in gene expression in the intact human heart. Downregulation of alpha-myosin heavy chain in hypertrophied, failing ventricular myocardium.

Lowes¹,

Minobe²,

Abraham³

et al. 1997

J. Clin. Invest.

455

288

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Using quantitative RT-PCR in RNA from right ventricular (RV) endomyocardial biopsies from intact nonfailing hearts, and subjects with moderate RV failure from primary pulmonary hypertension (PPH) or idiopathic dilated cardiomyopathy (IDC), we measured expression of genes involved in regulation of contractility or hypertrophy. Gene expression was also assessed in LV (left ventricular) and RV free wall and RV endomyocardium of hearts from end-stage IDC subjects undergoing heart transplantation or from nonfailing donors. In intact failing hearts, downregulation of ␤ 1 -receptor mRNA and protein, upregulation of atrial natriuretic peptide mRNA expression, and increased myocyte diameter indicated similar degrees of failure and hypertrophy in the IDC and PPH phenotypes. The only molecular phenotypic difference between PPH and IDC RVs was upregulation of

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Section: Discussionmentioning

confidence: 83%

Section: Measurement Of Mrna Abundance By Reverse Transcription-quantmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Changes in gene expression in the intact human heart. Downregulation of alpha-myosin heavy chain in hypertrophied, failing ventricular myocardium.

Lowes¹,

Minobe²,

Abraham³

et al. 1997

J. Clin. Invest.

455

288

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“…As a consequence of this increased "adrenergic drive" the cardiac ␤-AR 1 /G-protein/adenylyl cyclase pathway can become markedly desensitized. One major component of the desensitization is selective down-regulation of the dominant adrenergic receptor subtype within the human myocardium, the ␤ 1 -AR (1,(3)(4)(5). Recently, we (6) and others (7) have demonstrated that the observed decrease in ␤ 1 -adrenergic receptors in failing human heart is closely associated with a corresponding down-regulation of ␤ 1 AR mRNA.…”

mentioning

confidence: 97%

Regulation of the mRNA-binding Protein AUF1 by Activation of the β -Adrenergic Receptor Signal Transduction Pathway

Pende

Tremmel

DeMaria

et al. 1996

Journal of Biological Chemistry

150

130

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In both cell culture based model systems and in the failing human heart, beta-adrenergic receptors ( beta-AR) undergo agonist-mediated down-regulation. This decrease correlates closely with down-regulation of its mRNA, an effect regulated in part by changes in mRNA stability. Regulation of mRNA stability has been associated with mRNA-binding proteins that recognize A + U-rich elements within the 3'-untranslated regions of many mRNAs encoding proto-oncogene and cytokine mRNAs. We demonstrate here that the mRNA-binding protein, AUF1, is present in both human heart and in hamster DDT1-MF2 smooth muscle cells and that its abundance is regulated by beta-AR agonist stimulation. In human heart, AUF1 mRNA and protein was significantly increased in individuals with myocardial failure, a condition associated with increases in the beta-adrenergic receptor agonist norepinephrine. In the same hearts, there was a significant decrease (approximately 50%) in the abundance of beta1-AR mRNA and protein. In DDT1-MF2 cells, where agonist-mediated destabilization of beta2-AR mRNA was first described, exposure to beta-AR agonist resulted in a significant increase in AUF1 mRNA and protein (approximately 100%). Conversely, agonist exposure significantly decreased (approximately 40%) beta2-adrenergic receptor mRNA abundance. Last, we demonstrate that AUF1 can be immunoprecipitated from polysome-derived proteins following UV cross-linking to the 3'-untranslated region of the human beta1-AR mRNA and that purified, recombinant p37AUF1 protein also binds to beta1-AR 3'-untranslated region mRNA.

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“…Each receptor mediates positive inotropic and chronotropic responses to endogenous catecholamines and exogenously administered agonists (7). Most forms of congestive heart failure, including the "idiopathic" forms, are characterized by a diminished responsiveness to 13-agonists (8).…”

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confidence: 99%

Myocardial signaling defects and impaired cardiac function of a human beta 2-adrenergic receptor polymorphism expressed in transgenic mice.

Turki

Lorenz

Green

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

163

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A threonine to isoleucine polymorphism at amino acid 164 in the fourth transmembrane spanning domain of the 182-adrenergic receptor (,B2AR) is known to occur in the human population. The The human heart expresses both the ,i3AR and f32AR subtypes (6). Each receptor mediates positive inotropic and chronotropic responses to endogenous catecholamines and exogenously administered agonists (7). Most forms of congestive heart failure, including the "idiopathic" forms, are characterized by a diminished responsiveness to 13-agonists (8). As a probable consequence of elevated catecholamines (and perhaps of other factors as well), J31AR expression has been noted to be markedly reduced in patients with idiopathic dilated cardiomyopathy, a finding that has not been observed for the 32AR (8). The 132AR, then, may take on an even greater role in providing for cardiac responses to increased sympathetic drive or exogenous agonists under these circumstances. We have considered that if the Ile-164 variant is in fact dysfunctional in the heart, individuals harboring this receptor with heart failure may exhibit marked decompensation.The current study was undertaken to explore the relevance of the Ile-164 receptor in cardiac myocyte signaling at both the cellular and the whole organ levels. The strategy was to express in transgenic mice the human wild-type (32AR (wt 832AR) or the Ile-164 variant in a cardiac specific manner using the murine a myosin heavy chain (aMHC) promoter. In vitro and in vivo assessments of receptor function were then undertaken that revealed a substantial impairment imposed by this polymorphism in cellular as well as intact heart function. METHODSTransgenic Mice. Cardiac-specific expression of the 32AR in transgenic mice was achieved using the murine aMHC promoter (9). Briefly, the coding block of human wt 132AR cDNA was blunt-end ligated into an aMHC promoter construct (9) at the Sall site. To generate the Ile-164 polymorphism, oligonucleotide-directed site-specific mutagenesis was carried out on the wild-type template, substituting thymidine for cytidine at nucleic acid 491 as described (4). This mutated cDNA was also cloned into the aMHC SailI site, and the integrity of the two constructs was verified by dideoxy sequencing. Each was then digested by NotI and the liberated fragment was then isolated, purified, and used for injection into male pronuclei of embryos

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Regional Distribution of β-Adrenoceptors in the Human Heart

Cited by 171 publications

References 0 publications

Changes in gene expression in the intact human heart. Downregulation of alpha-myosin heavy chain in hypertrophied, failing ventricular myocardium.

Changes in gene expression in the intact human heart. Downregulation of alpha-myosin heavy chain in hypertrophied, failing ventricular myocardium.

Regulation of the mRNA-binding Protein AUF1 by Activation of the β -Adrenergic Receptor Signal Transduction Pathway

Myocardial signaling defects and impaired cardiac function of a human beta 2-adrenergic receptor polymorphism expressed in transgenic mice.

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