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J D Port

Publications and source records attributed to J D Port.

At least 19 recordsLinked to original sources
PubMed2001

Altered beta-adrenergic receptor gene regulation and signaling in chronic heart failure.

J. D. Port and M. R. Bristow. Altered Beta-adrenergic Receptor Gene Regulation and Signaling in Chronic Heart Failure. Journal of Molecular and Cellular Cardiology (2001) 33, 887-905. Beta adrenergic receptors (beta -ARs) are critical regulators of cardiac function in both normal and pathophysiological states. Under normal conditions, beta -ARs and their signaling pathways modulate both the rate and force of myocardial contraction and relaxation, allowing individuals to respond appropriately to physiological stress or exercise. However, in chronic heart failure, sustained activation of the beta -AR signaling pathways can have overtly negative biological consequences. This notion is reinforced by the positive outcomes of a number of clinical trials demonstrating the usefulness of beta-blocker therapy in chronic congestive heart failure. During the last few years, significant progress has been made in understanding the molecular biological basis of beta -AR function, both at the biochemical and genetic levels. In this review, the biological basis of adrenergic signaling and how this changes in heart failure is discussed. Aspects of adrenergic receptor pharmacology relevant to heart failure are reviewed, including the recently emerging differences described for beta(1)- v beta(2)-AR signaling pathways. Highlighting these differences is recent evidence that over-stimulation of the beta(1)-AR pathway in cardiac myocytes appears to be pro-apoptotic, whereas stimulation of the beta(2)-AR pathway may be anti-apoptotic. Overview of beta -AR gene regulation, transgenic models of beta -AR overexpression, and beta -AR polymorphisms as they relate to heart failure progression are also discussed.

Animals↗
PubMed2001

Bucindolol, a nonselective beta 1- and beta 2-adrenergic receptor antagonist, decreases beta-adrenergic receptor density in cultured embryonic chick cardiac myocyte membranes.

Bucindolol and carvedilol, nonselective beta1- and beta2-adrenergic receptor antagonists, have been widely used in clinical therapeutic trials of congestive heart failure. The aim of the current study was to investigate long-term effects of bucindolol or carvedilol on beta-adrenergic receptor protein and gene expression in cardiac myocytes. Embryonic chick cardiac myocytes were cultured and incubated with bucindolol (1 microM), carvedilol (1 microM), or norepinephrine (1 microM) for 24 h. 125I-iodocyanopindolol binding assays demonstrated that incubation with norepinephrine or bucindolol, but not carvedilol, significantly decreased beta-adrenergic receptor density in crude membranes prepared from the myocytes. Neither bucindolol nor carvedilol significantly stimulated adenylyl cyclase activity in membranes from drug-untreated cells. Unlike by norepinephrine, the receptor density reduction by bucindolol incubation was not accompanied by a change in beta1-adrenergic receptor messenger RNA abundance. A decrease in membrane beta-adrenergic receptor density without a change in cognate messenger RNA abundance was also observed in hamster DDT1 MF2 cell line incubated with bucindolol (1 microM, 24 h). We conclude that incubation with bucindolol, but not carvedilol, results in true reduction of beta-adrenergic receptor density in chick cardiac myocyte membranes by mechanisms that are distinct from those responsible for receptor density reduction by the agonist norepinephrine.

Adrenergic alpha-Agonists↗
PubMed2000

Purification and characterization of beta-adrenergic receptor mRNA-binding proteins.

Beta-adrenergic receptors (beta-ARs), like other G-protein-coupled receptors, can undergo post-transciptional regulation at the level of mRNA stability. In particular, the human beta(1)- and beta(2)-ARs and the hamster beta(2)-AR mRNA undergo beta-agonist-mediated destabilization. By UV cross-linking, we have previously described an approximately M(r) 36,000 mRNA-binding protein, betaARB, that binds to A/C+U-rich nucleotide regions within 3'-untranslated regions. Further, we have demonstrated previously that betaARB is immunologically distinct from AUF1/heterogeneous nuclear ribonucleoprotein (hnRNP) D, another mRNA-binding protein associated with destabilization of A+U-rich mRNAs (Pende, A., Tremmel, K. D., DeMaria, C. T., Blaxall, B. C., Minobe, W., Sherman, J. A., Bisognano, J., Bristow, M. R., Brewer, G., and Port, J. D. (1996) J. Biol. Chem. 271, 8493-8501). In this report, we describe the peptide composition of betaARB. Mass spectrometric analysis of an approximately M(r) 36,000 band isolated from ribosomal salt wash proteins revealed the presence of two mRNA-binding proteins, hnRNP A1, and the elav-like protein, HuR, both of which are known to bind to A+U-rich nucleotide regions. By immunoprecipitation, HuR appears to be the biologically dominant RNA binding component of betaARB. Although hnRNP A1 and HuR can both be immunoprecipitated from ribosomal salt wash proteins, the composition of betaARB (HuR alone versus HuR and hnRNP A1) appears to be dependent on the mRNA probe used. The exact role of HuR and hnRNP A1 in the regulation of beta-AR mRNA stability remains to be determined.

Amino Acid Sequence↗
PubMed2000

Deactivation of the sympathetic nervous system in patients with chronic congestive heart failure.

In this article, we review the basic biology, signal transduction pathways, and clinical pharmacology associated with cardiac beta-adrenergic receptors (beta-ARs) in the context of the use of beta-blocking agents in patients with chronic congestive heart failure. Adrenergic receptors, particularly the beta-AR subtypes (beta(1)-AR and beta(2)-AR), are known to play a critical role in the modulation of cardiac function, providing for both "adaptive" and "maladaptive" compensatory changes. In the context of exercise or self-preservation, the adrenergic nervous system, acting via beta-ARs permits an appropriately rapid, highly-dynamic increase in cardiac function. Conversely, in individuals with chronic congestive heart failure, the sustained, heightened activation of adrenergic nervous system, as manifested by increases in circulating catecholamines, results in down- regulation and desensitization of myocardial beta-ARs, and potentially, significant myocardial damage. A number of recent clinical trials have demonstrated a marked mortality benefit from using beta-blocking agents such as metoprolol and carvedilol in patients with heart failure. The pharmacologic properties of several of these drugs and some of the specifics of their usefulness and limitations are discussed herein.

Adrenergic beta-Antagonists↗
PubMed2000

Reversible leukoencephalopathy associated with re-infusion of DMSO preserved stem cells.

We report a case of posterior reversible leuko- encephalopathy (PRL) following the infusion of dimethylsulfoxide (DMSO) cryopreserved autologous stem cells in the setting of myeloablative chemotherapy in a patient with recurrent Ewing's sarcoma. Magnetic resonance (MR) imaging revealed white matter changes which resolved over the next 2 months. Bone Marrow Transplantation (2000) 26, 797-800.

Adolescent↗
PubMed2000

Differential expression and localization of the mRNA binding proteins, AU-rich element mRNA binding protein (AUF1) and Hu antigen R (HuR), in neoplastic lung tissue.

Modulation of gene expression at the level of mRNA stability has emerged as an important regulatory paradigm. In this context, differential expression of numerous mRNAs in normal versus neoplastic tissues has been described. Altered expression of these genes, at least in part, has been demonstrated to be at the level of mRNA stability. Two ubiquitously expressed mRNA binding proteins have recently been implicated in the stabilization (Hu antigen R/HuR) or destabilization (AU-rich element mRNA binding protein [AUF1]/heterogeneous nuclear ribonucleoprotein D) of target mRNAs. Further, their functional activity appears to require cytoplasmic localization. In the present study, we demonstrate a strong correlation between increased cytoplasmic expression of both AUF1 and HuR with urethane-induced neoplasia and with butylated hydroxytoluene-induced compensatory hyperplasia in mouse lung tissue. In addition, when compared with slower growing cells, rapidly growing neoplastic lung epithelial cell lines expressed a consistently higher abundance of both AUF1 and HuR proteins. Moreover, in nontumorigenic cell lines, both AUF1 and HuR protein abundance decreased with confluence and growth arrest. In contrast, in spontaneous transformants, AUF1 and HuR abundance was unaffected by changes in cell density. We suggest that growth-regulated alterations in AUF1 and HuR abundance may have pleiotropic effects on the expression of a number of highly regulated mRNAs and that this significantly impacts the onset, maintenance, and progression of the neoplastic phenotype. Mol. Carcinog. 28:76-83, 2000.

Animals↗
PubMed2000

New techniques in MR imaging of brain tumors.

The past decade has seen many new MR imaging techniques that have been applied to brain tumor imaging. As MR imaging is applied further to cellular and molecular imaging (e.g., imaging of gene transfer and expression), more possibilities for brain tumor diagnosis and treatment will become evident. The superior contrast, resolution, and lack of need for image coregistration suggest that MR imaging techniques may displace PET as the preeminent modality for studying brain and tumor physiology and chemistry for indications other than receptor-based imaging. Nevertheless, the new MR imaging techniques require further histologic, physiologic, and intraoperative validation in suitable animal models and in clinical studies, and should be used to complement PET. Application of echo-planar imaging and other fast imaging sequences can permit the merger of several MR imaging studies (e.g., perfusion imaging, DWI, and MRS(I) into a typical (1-hour) clinical time slot). Synergistic information provided by these new techniques might soon enable physicians to reach the ultimate goals of noninvasive tumor grading and avoidance of having to obtain a biopsy.

Adult↗
PubMed1999

Characterization of the binding of the RNA-binding protein AUF1 to the human AT(1) receptor mRNA.

An important mechanism of regulation of the expression of the AT(1) receptors is the modulation of the mRNA stability. AUF1, a human RNA-binding protein, may play an important role. Since AUF1 seems to bind to AU-rich regions of the 3'-untranslated region of the mRNAs, we verified the nucleotide sequence of human AT(1) receptor 3'-untranslated region and we found possible binding sites. In addition we evaluated the expression of the AUF1 protein in human vascular smooth muscle cells: the administration of both isoproterenol and angiotensin II induced a significant increase of total anti-AUF1 immunoreactive isoforms. At the same time angiotensin II induced a significant decrease in the AT(1) receptor mRNA abundance. Moreover, we found that recombinant human AUF1 protein binds to human AT(1) receptor riboprobes. The protein was able to bind to the distal portion of the 3'-untranslated region, and also to the coding region. Since the clinically relevant AT(1) receptor polymorphism is located in the 3'-untranslated region, we created two DNAs, corresponding to the A and C polymorphism, without any differences. Our data demonstrate the presence of AUF1 in human vascular smooth muscle cells and its modulation by activation of the beta-adrenergic and the AT(1) pathways, a and specific binding of AUF1 to the human AT(1) receptor mRNA, suggesting a role of this protein in the modulation of the AT(1) receptor expression.

3' Untranslated Regions↗
PubMed1999

Progressive multifocal leukoencephalopathy demonstrating contrast enhancement on MRI and uptake of thallium-201: a case report.

We describe a patient with AIDS who presented with focal neurological symptoms, and who had contrast-enhancing brain lesions on MRI which demonstrated increased thallium-201 uptake on SPECT. These findings were consistent with lymphoma; however, brain biopsy established a diagnosis of progressive multifocal leukoencephalopathy (PML). To our knowledge, this is the first reported case of PML with increased thallium-201 uptake on brain SPECT.

AIDS-Related Opportunistic Infections↗
PubMed1998

Agonist-mediated destabilization of human beta1-adrenergic receptor mRNA: role of the 3' untranslated translated region.

For proto-oncogenes and cytokines, regulation of gene expression at the level of mRNA stability is well established. In contrast, there is comparatively limited knowledge regarding this mechanism of regulation for G-protein-coupled receptors. To explore this process further, the human beta1-adrenergic receptor (AR) was stably expressed in tsAF8 cells. Treatment with beta-agonist decreased the half-life of beta1-AR mRNA by approximately 50%. Removal of the 3'UTR from the beta1-AR (coding region only) dramatically stabilized mRNA. Additionally, in a chimeric mRNA, the beta1-AR 3'UTR was able to target the normally highly stable beta-globin mRNA for accelerated decay. However, the chimera did not undergo agonist-mediated destabilization indicating that the 3'UTR may be "necessary but not sufficient" for agonist-mediated mRNA destabilization. Inhibition of translation significantly stabilized beta1-AR mRNA (approximately 2-fold); however, pretreatment of cells with beta-agonist prior to translational arrest produced the same degree of mRNA destabilization indicating that agonist-mediated destabilization may be independent of the translation process. Conversely, translational inhibition simultaneous with beta-agonist exposure abrogated agonist-mediated destabilization indicating a dependence on de novo protein synthesis.

3' Untranslated Regions↗
PubMed1998

Beta-adrenergic blockade in chronic heart failure.

In summary, beta-blockade is currently the most promising "new" treatment undergoing Phase III testing in chronic heart failure. Multiple studies on the effects of these agents on LV function and chamber characteristics as well as limited survival data strongly suggest that these agents produce a beneficial effect on the natural history of heart failure. If this promise is borne out in the currently active or planned large-scale clinical trials, this form of therapy will emerge as the most valuable treatment available for chronic heart failure.

Adrenergic beta-Antagonists↗
PubMed1997

Selective downregulation of the angiotensin II AT1-receptor subtype in failing human ventricular myocardium.

BACKGROUND: The regulation of angiotensin II receptors and the two major subtypes (AT1 and AT2) in chronically failing human ventricular myocardium has not been previously examined. METHODS AND RESULTS: Angiotensin II receptors were measured by saturation binding of 125I-[Sar1,Ile8]angiotensin II in crude membranes from nonfailing (n = 19) and failing human left ventricles with idiopathic dilated cardiomyopathy (IDC; n = 31) or ischemic cardiomyopathy (ISC; n = 21) and membranes from a limited number of right ventricles in each category. The AT1 and AT2 fractions were determined by use of an AT1-selective antagonist, losartan. beta-Adrenergic receptors were also measured by binding of 125I-iodocyanopindolol with the beta 1 and beta 2 fractions determined by use of a beta 1-selective antagonist, CGP20712A, AT1 but not AT2 density was significantly decreased in the combined (IDC + ISC) failing left ventricles (nonfailing: AT1 4.66 +/- 0.48, AT2 2.73 +/- 0.39; failing: AT1 3.20 +/- 0.29, AT2 2.70 +/- 0.33 fmol/mg protein; mean +/- SE). The decrease in AT1 density was greater in the IDC than in the ISC left ventricles (IDC: 2.73 +/- 0.40, P < .01; ISC: 3.89 +/- 0.39 fmol/mg protein, P = NS versus nonfailing). beta 1 but not beta 2 density was decreased in the failing left ventricles. AT1 density was correlated with beta 1 density in all left ventricles (r = .43). AT1 density was also decreased in IDC right ventricles. In situ reverse transcription-polymerase chain reaction in sections of nonfailing and failing ventricles indicated that AT1 mRNA was present in both myocytes and nonmyocytes. CONCLUSIONS: AT1 receptors are selectively downregulated in failing human ventricles, similar to the selective downregulation of beta 1 receptors. The relative lack of AT1 downregulation in ISC hearts may be related to differences in the degree of ventricular dysfunction.

Adult↗
PubMed1996

Cardiac adrenergic receptor effects of carvedilol.

Carvedilol is an adrenoceptor antagonist which modulates the activity not only of beta 1 and beta 2 but also of alpha 1 adrenergic receptors present on the cell surface membrane of the human cardiac myocyte. In the heart, carvedilol has approximately 7 times higher potency for beta 1 and beta 2 adrenoceptors, but in the doses 50-100 mg . day-1 used in clinical practice, it is essentially non-selective. In human myocardial preparations and in cultured heart cells, carvedilol has no intrinsic sympathomimetic activity but is able to identify high affinity agonist-binding receptors whose pharmacological signature is reduction in binding by incubation with guanine nucleotides (guanine nucleotide-modulatable binding). This property is more prominent for the human beta 2 than for the beta 1 adrenoceptor. The property of gaunine nucleotide-modulatable binding for carvedilol and structurally related bucindolol correlates with their ability to directly down-regulate beta 1-like receptors present in cultured chick myocytes, and with a lack of reversal of down-regulation of cardiac beta-receptors in patients with heart failure. Carvedilol does not exhibit high levels of inverse agonist activity, which may contribute to its good tolerability in subjects with heart failure. These data indicate that carvedilol produces a high degree of adrenergic receptor blockade in the failing human heart, and does not re-sensitize the beta-receptor pathway to stimulation by adrenergic agonists.

Adrenergic beta-Antagonists↗
PubMed1995

Cardiac beta-adrenergic neuroeffector systems in acute myocardial dysfunction related to brain injury. Evidence for catecholamine-mediated myocardial damage.

BACKGROUND: Ten percent to 20% of potential cardiac donors with brain injury and no previous cardiac history have myocardial dysfunction. We assessed components of the beta-receptor-G-protein-adenylyl cyclase complex as well as the contractile response in 10 explanted acutely failing human hearts (donor heart dysfunction [DHD]) and compared the results with 13 age-matched nonfailing (NF) organ donor controls. METHODS AND RESULTS: As measured by echocardiography, all DHD hearts exhibited a decreased shortening fraction (16 +/- 2%, mean +/- SEM). Although total and subpopulation beta-receptor densities measured by [125I]iodocyanopindolol (ICYP) were similar in the DHD and NF groups, DHD hearts exhibited a 30% decrease in maximum isoproterenol-stimulated adenylyl cyclase activity and a 50% decrease in the maximal response to zinterol. DHD hearts also exhibited decreases in adenylyl cyclase maximal stimulation by forskolin (211 +/- 25 [DHD] versus 295 +/- 23 [NF] pmol cAMP.min-1.mg-1, P < .05) and 5'-guanylylimidodiphosphate (12.5 +/- 1.8 [DHD] versus 19.6 +/- 3.2 [NF] pmol cAMP.min-1.mg-1, P < .05), but there was no significant decrease in adenylyl cyclase stimulation by Mn2+, a direct activator of adenylyl cyclase. Right ventricular trabeculae removed from DHD hearts exhibited a profound decrease in the contractile response to isoproterenol (8.7 +/- 1 [DHD] versus 22 +/- 2 [NF] mN, P < .001) as well as reduced calcium responses (7.2 +/- 1.6 [DHD] versus 14 +/- 3 [NF] mN, P = .03). Morphological examination of two hearts revealed some ultrastructural evidence suggestive of catecholamine-mediated injury, but there was no difference in tissue creatine kinase activity between the two groups. CONCLUSIONS: Compared with NF hearts, DHD hearts exhibit marked uncoupling of beta 1- and beta 2-adrenergic receptors from adenylyl cyclase and contractile response stimulation as well as decreased intrinsic systolic function. Thus, acute myocardial dysfunction accompanying brain injury is characterized by marked alterations in beta-adrenergic signal transduction as well as changes in the contractile apparatus, and this profile is markedly different from what occurs in the chronically failing human heart.

Adenylyl Cyclases↗