DOCSLIB.ORG

(12) Patent Application Publication (10) Pub. No.: US 2013/0203827 A1 Sucharov Et Al

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(12) Patent Application Publication (10) Pub. No.: US 2013/0203827 A1 Sucharov Et Al US 20130203827A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0203827 A1 Sucharov et al. (43) Pub. Date: Aug. 8, 2013 (54) POLYMORPHISMS IN THE PDE3A GENE Related U.S. Application Data (75) Inventors: Carmen Sucharov, Superior, CO (US); (60) Pygal application No. 61/241,730, filed on Sep. Michael Bristow, Englewood, CO (US); Matthew Taylor, Denver, CO (US); Dobromir Slavov, Aurora, CO (US) Publication Classification (73) Assignee: The Regents of the University of ( 51) Int. Cl. Colorado. a Body, Denver, CO (US) CI2O I/68 (2006.01) (52) U.S. Cl. (21) Appl. No.: 13/395,311 CPC .................................... CI2O I/6883 (2013.01) USPC ............................... 514/392:435/6.11:506/9 (22) PCT Filed: Sep. 13, 2010 (57) ABSTRACT (86). PCT No.: PCT/US10/48629 Embodiments of the invention are directed to identifying or S371 (c)(1), treating a patient that would benefit from phosphodiesterase (2), (4) Date: Nov. 5, 2012 inhibitor therapy. Patent Application Publication Aug. 8, 2013 Sheet 1 of 8 US 2013/0203827 A1 f Patent Application Publication Aug. 8, 2013 Sheet 2 of 8 US 2013/0203827 A1 ¿Q?TGJJES??—?VLVSVLØVVLVOV/91 LJOO‘V=H 1.JOSБV=C) JLJOV=W Patent Application Publication Aug. 8, 2013 Sheet 3 of 8 US 2013/0203827 A1 s O V C) S O S X O g C i2 E O O. O. O. O 9 o O O. O. O. O. O. O. O. OO N CO N (f) on V Ouluoo Sugo9% 'AAW eSeuegon emele Patent Application Publication Aug. 8, 2013 Sheet 4 of 8 US 2013/0203827 A1 f f f O o C coa S.e s 3s o co st N v- vs ver re OuluOO eOJO% "AIAIOW eSeleon enee Patent Application Publication Aug. 8, 2013 Sheet 5 of 8 US 2013/0203827 A1 Sene S9. |Sieme WNAu l-AB Patent Application Publication Aug. 8, 2013 Sheet 6 of 8 US 2013/0203827 A1 activated Transcriptionis repressed Transcriptionis Patent Application Publication Aug. 8, 2013 Sheet 7 of 8 US 2013/0203827 A1 m s O - o 9 S - O s s f O s H genegr)(2)(a)(2)(s) Sene S9. 5 SeAe WNAUW9C 2 SeAe S9. SeAe WNAU W9BO Patent Application Publication Aug. 8, 2013 Sheet 8 of 8 US 2013/0203827 A1 s s s SN o Sieme S9. |SeAe WNUlu W9C US 2013/0203827 A1 Aug. 8, 2013 POLYMORPHSMS IN THE PDE3A GENE PDE3A levels and reduced response to treatment, commonly 0001. This application claims benefit of priority to U.S. known as pharmacological tolerance. Provisional Application Ser. No. 61/241,730, filed Sep. 11, 0007 Certain embodiments are directed to methods for 2009, the entire contents of which are hereby incorporated by treating a patient with heart failure comprising treating the reference. patient with an effective amount of a PDE3A inhibitor after the patient is determined to be homozygous for an insertional BACKGROUND OF THE INVENTION polymorphism comprising an Evi-1 binding site in the pro moter of the phosphodiesterase type 3A (PDE3A) gene. The 0002 I. Field of the Invention Evi-1 insertion polymorphism refers to a nucleic acid 0003 Embodiments of this invention are directed gener sequence inserted in the promoter of PDE3A comprising a ally to biology, molecular genetics, and medicine. Certain nucleic acid sequence that is 85,90, 95, 98, to 100% identical embodiments are directed to identifying a patient that would to the nucleic acid sequence of SEQ ID NO:2. In certain benefit from phosphodiesterase inhibitor therapy. aspects the insertional polymorphism comprises an ectotro 0004 II. Background pic viral integration site-1 protein (Evi-1) binding site. In a 0005 Cardiac hypertrophy in response to an increased further aspects the Evi-1 binding site comprises a 5, 10, 15 to workload imposed on the heart is a fundamental adaptive 10, 15, 25, 29 nucleotides or more, including all values and mechanism. It is a specialized process reflecting a quantita ranges there between of the nucleotide sequence of SEQID tive increase in cell size and mass (rather than cell number) as NO:2. the result of any, or a combination of neural, endocrine or 0008. In certain aspects a PDE3A inhibitor is aminone, mechanical stimuli. When heart failure occurs, the left ven cilostazol, milrinone, quaZinone, SiguaZodan, trequinsin, or tricle usually is hypertrophied and dilated and indices of enoximone. In a further aspect the PDE3A inhibitor is enoxi systolic function, such as ejection fraction, are reduced. mone. The PDE3A inhibitor can be administered at a dose of Clearly, the cardiac hypertrophic response is a complex Syn 1, 5, 10, 15.20, 25, 30,35, 40, 45, 50 mg to 40, 50, 60, 70,80, drome and the elucidation of the pathways leading to cardiac 90, 100, or 150 mg, including all values and ranges there hypertrophy and systolic dysfunction will be beneficial in the between. In certain aspects the PDE3A inhibitor is adminis treatment of heart disease resulting from various stimuli. tered 1, 2, 3, 4, 5 or more times a day, a week, or a month, There remains a need for additional treatments for patients including all values and ranges there between. suffering from heart failure. 0009 Certain embodiments are directed to methods for evaluating a heart failure patient comprising analyzing a bio SUMMARY OF THE INVENTION logical sample from the patient for the presence of an ecto 0006 Chronic activation of the f-Adrenergic Receptor tropic viral integration site-1 protein (Evi-1) binding site (B-AR) can have deleterious effects on the heart, and animal deletion or insertional polymorphism in the promoter of one models over-expressing the B-AR develop heart failure. In the or more phosphodiesterase type 3A (PDE3A) genes of the classical B-AR pathway, activation of the receptor results in patient, wherein a patient determined to be homozygous for increased cyclic AMP (cAMP) levels. However, B-ARs are the insertional polymorphism is responsive to PDE3A inhibi desensitized in the failing heart and cAMP levels are tor therapy. decreased. Phosphodiesterase 3A (PDE3A) hydrolyzes 0010. In certain aspects the methods described herein can cAMP in certain Subcellular compartments in cardiac myo further comprise obtaining a biological sample from the cytes, regulating cAMP levels and Subsequent protein kinase patient. A biological sample can be a blood sample, a buccal A mediated cell signaling. Since cAMP is reduced in certain Smear, a tissue sample, or a primary culture of Somatic cells important cardiac myocyte Subcellular compartments such as from the patient. In certain aspects analyzing the sample the microdomain occupied by phospholamban and SR Ca2+ comprises performing nucleic acid sequencing, restriction ATPase, it has been postulated that PDE3A inhibition will digestion, allele-specific nucleic acid amplification, single benefit the heart failure clinical syndrome by restoring cAMP Stranded conformational polymorphism analysis, or allele levels in the phospholamban microdomain/suncellular com specific hybridization analysis. The methods described partment. However, a recently published large clinical trial herein can further comprising preparing a report containing showed benefits of a PDE3 inhibitor on only a subset of information regarding the genotype of one or more PDE3A patients. Here we show that the promoter region of PDE3A genes of the patient. In a further aspect the patient has symp contains a 29 nucleotide insertional polymorphism (SEQID toms of or has been diagnosed with heart failure. In still a NO:2) that renders the PDE3A promoter non-responsive to further aspect the patient is determined to be homozygous for increased cAMP levels. The inventors demonstrate that the insertional polymorphism in the PDE3A gene and is sub increased cAMP levels in the cardiac cell, mediated by iso sequently treated with a PDE3A inhibitor. proterenol, a cAMP analogue or PDE3A inhibition, results in 0011. In certain embodiments the patient is determined increased promoter activity when the promoter construct not to be homozygous for the insertional polymorphism in the lacks the 29 nucleotide sequence. However, promoteractivity PDE3A gene and is subsequently treated with a non-PDE3A does not go up when the sequence is present. Similarly, inhibitor treatment. mRNA levels for heart failure patients containing the inser 0012. Further embodiments are directed to methods for tion polymorphism were not up-regulated in response to evaluating a patient having or at risk of developing heart PDE3A inhibition treatment while mRNA levels for patients failure for responsiveness to phosphodiesterase inhibitor lacking this region were up-regulated 2-fold in response to therapy comprising obtaining a determination of the patients treatment. These results indicate that only patients who are genotype for an insertional polymorphism in a phosphodi homozygous for the insertion should be treated with a esterase type 3A (PDE3A) gene, wherein homozygosity for PDE3A inhibition. Inhibition of PDE3A in other patients will the insertional polymorphism is predictive of responsiveness create a positive feedback loop that will result in increased to phosphodiesterase inhibitor therapy for treating heart fail US 2013/0203827 A1 Aug. 8, 2013 ure in the patient. In certain aspects the nucleic acid sequence TGACTAGCTG). A second primer can comprise the nucleic insertion comprises an ectotropic viral integration site-1 pro acid sequence of SEQID NO:7 (GCCAAAAGGAGATCCT tein (Evi-1) binding site. In a further aspect the Evi-1 binding TGAGAT). site has a nucleic acid sequence that is 85,90, 95, 98, or 100% 0016 Certain embodiments are directed to a nucleic acid identical to the nucleic acid sequence of SEQID NO:2. The probe that specifically hybridizes to a phosphodiesterase type methods can include obtaining a patient history. In certain 3A nucleic acid comprising nucleotides 274 to 302 of SEQID aspects this includes determination of the patient’s genotype NO:3 or a nucleic acid that is 85,90, 95, 98, or 1005 identical for an insertional polymorphism in a phosphodiesterase type to SEQID NO:2.
Load more

Recommended publications
  • Analyses of PDE-Regulated Phosphoproteomes Reveal Unique and Specific Camp-Signaling Modules in T Cells
    Analyses of PDE-regulated phosphoproteomes reveal unique and specific cAMP-signaling modules in T cells Michael-Claude G. Beltejara, Ho-Tak Laua, Martin G. Golkowskia, Shao-En Onga, and Joseph A. Beavoa,1 aDepartment of Pharmacology, University of Washington, Seattle, WA 98195 Contributed by Joseph A. Beavo, May 28, 2017 (sent for review March 10, 2017; reviewed by Paul M. Epstein, Donald H. Maurice, and Kjetil Tasken) Specific functions for different cyclic nucleotide phosphodiester- to bias T-helper polarization toward Th2, Treg, or Th17 pheno- ases (PDEs) have not yet been identified in most cell types. types (13, 14). In a few cases increased cAMP may even potentiate Conventional approaches to study PDE function typically rely on the T-cell activation signal (15), particularly at early stages of measurements of global cAMP, general increases in cAMP- activation. Recent MS-based proteomic studies have been useful dependent protein kinase (PKA), or the activity of exchange in characterizing changes in the phosphoproteome of T cells under protein activated by cAMP (EPAC). Although newer approaches various stimuli such as T-cell receptor stimulation (16), prosta- using subcellularly targeted FRET reporter sensors have helped glandin signaling (17), and oxidative stress (18), so much of the define more compartmentalized regulation of cAMP, PKA, and total Jurkat phosphoproteome is known. Until now, however, no EPAC, they have limited ability to link this regulation to down- information on the regulation of phosphopeptides by PDEs has stream effector molecules and biological functions. To address this been available in these cells. problem, we have begun to use an unbiased mass spectrometry- Inhibitors of cAMP PDEs are useful tools to study PKA/EPAC- based approach coupled with treatment using PDE isozyme- mediated signaling, and selective inhibitors for each of the 11 PDE – selective inhibitors to characterize the phosphoproteomes of the families have been developed (19 21).
    [Show full text]
  • Phosphodiesterase Inhibitors: Their Role and Implications
    International Journal of PharmTech Research CODEN (USA): IJPRIF ISSN : 0974-4304 Vol.1, No.4, pp 1148-1160, Oct-Dec 2009 PHOSPHODIESTERASE INHIBITORS: THEIR ROLE AND IMPLICATIONS Rumi Ghosh*1, Onkar Sawant 1, Priya Ganpathy1, Shweta Pitre1 and V.J.Kadam1 1Dept. of Pharmacology ,Bharati Vidyapeeth’s College of Pharmacy, University of Mumbai, Sector 8, CBD Belapur, Navi Mumbai -400614, India. *Corres.author: rumi 1968@ hotmail.com ABSTRACT: Phosphodiesterase (PDE) isoenzymes catalyze the inactivation of intracellular mediators of signal transduction such as cAMP and cGMP and thus have pivotal roles in cellular functions. PDE inhibitors such as theophylline have been employed as anti-asthmatics since decades and numerous novel selective PDE inhibitors are currently being investigated for the treatment of diseases such as Alzheimer’s disease, erectile dysfunction and many others. This review attempts to elucidate the pharmacology, applications and recent developments in research on PDE inhibitors as pharmacological agents. Keywords: Phosphodiesterases, Phosphodiesterase inhibitors. INTRODUCTION Alzheimer’s disease, COPD and other aliments. By cAMP and cGMP are intracellular second messengers inhibiting specifically the up-regulated PDE isozyme(s) involved in the transduction of various physiologic with newly synthesized potent and isoezyme selective stimuli and regulation of multiple physiological PDE inhibitors, it may possible to restore normal processes, including vascular resistance, cardiac output, intracellular signaling selectively, providing therapy with visceral motility, immune response (1), inflammation (2), reduced adverse effects (9). neuroplasticity, vision (3), and reproduction (4). Intracellular levels of these cyclic nucleotide second AN OVERVIEW OF THE PHOSPHODIESTERASE messengers are regulated predominantly by the complex SUPER FAMILY superfamily of cyclic nucleotide phosphodiesterase The PDE super family is large, complex and represents (PDE) enzymes.
    [Show full text]
  • Phosphodiesterase Inhibitors: Could They Be Beneficial for the Treatment of COVID-19?
    International Journal of Molecular Sciences Review Phosphodiesterase Inhibitors: Could They Be Beneficial for the Treatment of COVID-19? Mauro Giorgi 1,*, Silvia Cardarelli 2, Federica Ragusa 3, Michele Saliola 1, Stefano Biagioni 1, Giancarlo Poiana 1 , Fabio Naro 2 and Mara Massimi 3,* 1 Department of Biology and Biotechnology “Charles Darwin”, Sapienza University of Rome, 00185 Rome, Italy; [email protected] (M.S.); [email protected] (S.B.); [email protected] (G.P.) 2 Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University, 00185 Rome, Italy; [email protected] (S.C.); [email protected] (F.N.) 3 Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; [email protected] * Correspondence: [email protected] (M.G.); [email protected] (M.M.) Received: 10 July 2020; Accepted: 24 July 2020; Published: 27 July 2020 Abstract: In March 2020, the World Health Organization declared the severe acute respiratory syndrome corona virus 2 (SARS-CoV2) infection to be a pandemic disease. SARS-CoV2 was first identified in China and, despite the restrictive measures adopted, the epidemic has spread globally, becoming a pandemic in a very short time. Though there is growing knowledge of the SARS-CoV2 infection and its clinical manifestations, an effective cure to limit its acute symptoms and its severe complications has not yet been found. Given the worldwide health and economic emergency issues accompanying this pandemic, there is an absolute urgency to identify effective treatments and reduce the post infection outcomes. In this context, phosphodiesterases (PDEs), evolutionarily conserved cyclic nucleotide (cAMP/cGMP) hydrolyzing enzymes, could emerge as new potential targets.
    [Show full text]
  • Various Subtypes of Phosphodiesterase Inhibitors Differentially Regulate Pulmonary Vein and Sinoatrial Node Electrical Activities
    EXPERIMENTAL AND THERAPEUTIC MEDICINE 19: 2773-2782, 2020 Various subtypes of phosphodiesterase inhibitors differentially regulate pulmonary vein and sinoatrial node electrical activities YUNG‑KUO LIN1,2*, CHEN‑CHUAN CHENG3*, JEN‑HUNG HUANG1,2, YI-ANN CHEN4, YEN-YU LU5, YAO‑CHANG CHEN6, SHIH‑ANN CHEN7 and YI-JEN CHEN1,8 1Department of Internal Medicine, Division of Cardiovascular Medicine, Wan Fang Hospital; 2Department of Internal Medicine, Division of Cardiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11696; 3Division of Cardiology, Chi‑Mei Medical Center, Tainan 71004; 4Division of Nephrology; 5Division of Cardiology, Department of Internal Medicine, Sijhih Cathay General Hospital, New Taipei 22174; 6Department of Biomedical Engineering, National Defense Medical Center, Taipei 11490; 7Heart Rhythm Center and Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217; 8Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11696, Taiwan, R.O.C. Received May 16, 2019; Accepted January 9, 2020 DOI: 10.3892/etm.2020.8495 Abstract. Phosphodiesterase (PDE)3-5 are expressed in 20.7±4.6%, respectively. In addition, milrinone (1 and 10 µM) cardiac tissue and play critical roles in the pathogenesis of induced the occurrence of triggered activity (0/8 vs. 5/8; heart failure and atrial fibrillation. PDE inhibitors are widely P<0.005) in PVs. Rolipram increased PV spontaneous activity used in the clinic, but their effects on the electrical activity by 7.5±1.3‑9.5±4.0%, although this was not significant, and did of the heart are not well understood. The aim of the present not alter SAN spontaneous activity.
    [Show full text]
  • Metabolic Enzyme/Protease
    Inhibitors, Agonists, Screening Libraries www.MedChemExpress.com Metabolic Enzyme/Protease Metabolic pathways are enzyme-mediated biochemical reactions that lead to biosynthesis (anabolism) or breakdown (catabolism) of natural product small molecules within a cell or tissue. In each pathway, enzymes catalyze the conversion of substrates into structurally similar products. Metabolic processes typically transform small molecules, but also include macromolecular processes such as DNA repair and replication, and protein synthesis and degradation. Metabolism maintains the living state of the cells and the organism. Proteases are used throughout an organism for various metabolic processes. Proteases control a great variety of physiological processes that are critical for life, including the immune response, cell cycle, cell death, wound healing, food digestion, and protein and organelle recycling. On the basis of the type of the key amino acid in the active site of the protease and the mechanism of peptide bond cleavage, proteases can be classified into six groups: cysteine, serine, threonine, glutamic acid, aspartate proteases, as well as matrix metalloproteases. Proteases can not only activate proteins such as cytokines, or inactivate them such as numerous repair proteins during apoptosis, but also expose cryptic sites, such as occurs with β-secretase during amyloid precursor protein processing, shed various transmembrane proteins such as occurs with metalloproteases and cysteine proteases, or convert receptor agonists into antagonists and vice versa such as chemokine conversions carried out by metalloproteases, dipeptidyl peptidase IV and some cathepsins. In addition to the catalytic domains, a great number of proteases contain numerous additional domains or modules that substantially increase the complexity of their functions.
    [Show full text]
  • Therapeutic Opportunities in Colon Cancer Focus on Phosphodiesterase Inhibitors
    Life Sciences 230 (2019) 150–161 Contents lists available at ScienceDirect Life Sciences journal homepage: www.elsevier.com/locate/lifescie Review article Therapeutic opportunities in colon cancer: Focus on phosphodiesterase inhibitors T ⁎ Ankita Mehta, Bhoomika M. Patel Institute of Pharmacy, Nirma University, Ahmedabad, India ARTICLE INFO ABSTRACT Keywords: Despite novel technologies, colon cancer remains undiagnosed and 25% of patients are diagnosed with meta- Phosphodiesterases static colon cancer. Resistant to chemotherapeutic agents is one of the major problems associated with treating cAMP colon cancer which creates the need to develop novel agents targeting towards newer targets. A phosphodies- cGMP terase is a group of isoenzyme, which, hydrolyze cyclic nucleotides and thereby lowers intracellular levels of Adenylate cyclase cAMP and cGMP leading to tumorigenic effects. Many in vitro and in vivo studies have confirmed increased PDE Guanylate cyclase expression in different types of cancers including colon cancer. cAMP-specific PDE inhibitors increase in- Colon cancer tracellular cAMP that leads to activation of effector molecules-cAMP-dependent protein kinase A, exchange protein activated by cAMP and cAMP gated ion channels. These molecules regulate cellular responses and exert its anticancer role through different mechanisms including apoptosis, inhibition of angiogenesis, upregulating tumor suppressor genes and suppressing oncogenes. On the other hand, cGMP specific PDE inhibitors exhibit anticancer effects through cGMP dependent protein kinase and cGMP dependent cation channels. Elevation in cGMP works through activation of caspases, suppression of Wnt/b-catenin pathway and TCF transcription leading to inhibition of CDK and survivin. These studies point out towards the fact that PDE inhibition is as- sociated with anti-proliferative, anti-apoptotic and anti-angiogenic pathways involved in its anticancer effects in colon cancer.
    [Show full text]
  • Dual PDE34 and PDE4 Inhibitors
    Basic & Clinical Pharmacology & Toxicology Doi: 10.1111/bcpt.12209 MiniReview Dual PDE3/4 and PDE4 Inhibitors: Novel Treatments For COPD and Other Inflammatory Airway Diseases Katharine H. Abbott-Banner1 and Clive P. Page2 1Verona Pharma plc, London, UK and 2Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King’s College London, London, UK (Received 2 December 2013; Accepted 30 January 2014) Abstract: Selective phosphodiesterase (PDE) 4 and dual PDE3/4 inhibitors have attracted considerable interest as potential thera- peutic agents for the treatment of respiratory diseases, largely by virtue of their anti-inflammatory (PDE4) and bifunctional bron- chodilator/anti-inflammatory (PDE3/4) effects. Many of these agents have, however, failed in early development for various reasons, including dose-limiting side effects when administered orally and lack of sufficient activity when inhaled. Indeed, only one selective PDE4 inhibitor, the orally active roflumilast-n-oxide, has to date received marketing authorization. The majority of the compounds that have failed were, however, orally administered and non-selective for either PDE3 (A,B) or PDE4 (A,B,C,D) subtypes. Developing an inhaled dual PDE3/4 inhibitor that is rapidly cleared from the systemic circulation, potentially with sub- type specificity, may represent one strategy to improve the therapeutic index and also exhibit enhanced efficacy versus inhibition of either PDE3 or PDE4 alone, given the potential positive interactions with regard to anti-inflammatory and bronchodilator effects that have been observed pre-clinically with dual inhibition of PDE3 and PDE4 compared with inhibition of either isozyme alone. This MiniReview will summarize recent clinical data obtained with PDE inhibitors and the potential for these drugs to treat COPD and other inflammatory airways diseases such as asthma and cystic fibrosis.
    [Show full text]
  • Dual Activation of Phosphodiesterase 3 and 4 Regulates Basal Cardiac Pacemaker Function and Beyond
    International Journal of Molecular Sciences Review Dual Activation of Phosphodiesterase 3 and 4 Regulates Basal Cardiac Pacemaker Function and Beyond Tatiana M. Vinogradova * and Edward G. Lakatta Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institute of Health, 251 Bayview Boulevard, Baltimore, MD 21224, USA; [email protected] * Correspondence: [email protected] Abstract: The sinoatrial (SA) node is the physiological pacemaker of the heart, and resting heart rate in humans is a well-known risk factor for cardiovascular disease and mortality. Consequently, the mechanisms of initiating and regulating the normal spontaneous SA node beating rate are of vital importance. Spontaneous firing of the SA node is generated within sinoatrial nodal cells (SANC), which is regulated by the coupled-clock pacemaker system. Normal spontaneous beating of SANC is driven by a high level of cAMP-mediated PKA-dependent protein phosphorylation, which rely on the balance between high basal cAMP production by adenylyl cyclases and high basal cAMP degradation by cyclic nucleotide phosphodiesterases (PDEs). This diverse class of enzymes includes 11 families and PDE3 and PDE4 families dominate in both the SA node and cardiac myocardium, degrading cAMP and, consequently, regulating basal cardiac pacemaker function and excitation-contraction coupling. In this review, we will demonstrate similarities between expression, distribution, and colocalization of various PDE subtypes in SANC and cardiac myocytes of different species, including humans, focusing on PDE3 and PDE4. Here, we will describe specific targets of the coupled-clock pacemaker system modulated by dual PDE3 + PDE4 activation and provide Citation: Vinogradova, T.M.; Lakatta, evidence that concurrent activation of PDE3 + PDE4, operating in a synergistic manner, regulates the E.G.
    [Show full text]
  • Cyclic-3′,5′-Nucleotide Phosphodiesterase
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Kidney International, Vol. 55 (1999), pp. 29±62 PERSPECTIVES IN BASIC SCIENCE Cyclic-39,59-nucleotide phosphodiesterase isozymes in cell biology and pathophysiology of the kidney THOMAS P. DOUSA Renal Pathophysiology Laboratory, Department of Physiology and Biophysics, Mayo Clinic and Foundation, Mayo Medical School, Rochester, Minnesota, USA Cyclic-39,59-nucleotide phosphodiesterase isozymes in cell biology and through intracellular mediation of a speci®c adenine nu- pathophysiology of the kidney. Investigations of recent years revealed cleotide, cyclic-39,59-adenosine monophosphate (cAMP), that isozymes of cyclic-39,59-nucleotide phosphodiesterase (PDE) are a critically important component of the cyclic-39,59-adenosine mono- and the era of second messengers and intracellular sig- phosphate (cAMP) protein kinase A (PKA) signaling pathway. The naling was born. Shortly after the discovery of cAMP, an superfamily of cyclic-39,59-phosphodiesterase (PDE) isozymes consists analogous guanine nucleotide, cyclic-39,59-GMP (cGMP), of at least nine gene families (types): PDE1 to PDE9. Some PDE families are very diverse and consist of several subtypes and numerous was identi®ed [2], and this nucleotide turned out to play PDE isoform-splice variants. PDE isozymes differ in molecular struc- a similarÐalbeit not identicalÐrole in cellular signaling ture, catalytic properties, intracellular regulation and location, and sensitivity to selective inhibitors, as well as differential expression in as cAMP [3]. Since then, a number of other second mes- various cell types. A number of type-speci®c ªsecond-generationº PDE sengers and related components of intracellular signaling inhibitors have been developed.
    [Show full text]
  • Inhibition of PDE3B Augments PDE4 Inhibitor-Induced Apoptosis in a Subset of Patients with Chronic Lymphocytic Leukemia1
    Vol. 8, 589–595, February 2002 Clinical Cancer Research 589 Inhibition of PDE3B Augments PDE4 Inhibitor-induced Apoptosis in a Subset of Patients with Chronic Lymphocytic Leukemia1 Eunyi Moon, Richard Lee, Richard Near, benefit in a subset of relatively PDE4-inhibitor resistant Lewis Weintraub, Sharon Wolda, and CLL patients. Adam Lerner2 INTRODUCTION Department of Medicine, Section of Hematology and Oncology, Boston Medical Center, Boston, Massachusetts 02118 [E. M., R. L., Methylxanthines such as theophylline, a drug widely used R. N., L. W., A. L.]; Department of Pathology, Boston University for treatment of asthma and neonatal apnea, induce apoptosis in School of Medicine, Boston, Massachusetts 02118 [A. L.]; and ICOS CLL3 cells in vitro (1). The sensitivity of CLL cells to other Corporation, Bothell, Washington 98021 [S. W.] agents that raise cAMP levels such as dibutyryl cAMP or forskolin has suggested that the proapoptotic activity of meth- ABSTRACT ylxanthines may arise, at least in part, because of their activity as nonspecific cyclic nucleotide PDE inhibitors (2). A Phase II Purpose: cAMP phosphodiesterase (PDE) 4 is a family clinical trial by Binet et al. (3) in patients with chlorambucil- of enzymes the inhibition of which induces chronic lympho- resistant CLL, as well as case reports (4), have suggested that cytic leukemia (CLL) apoptosis. However, leukemic cells adding theophylline to chlorambucil may be of clinical value in from a subset of CLL patients are relatively resistant to this disease. The efficacy of theophylline as a single agent in treatment with the PDE4 inhibitor rolipram, particularly early stage CLL is currently being examined by Makower et al.
    [Show full text]
  • A Molecular Mechanism of Action of Theophylline: Induction of Histone Deacetylase Activity to Decrease Inflammatory Gene Expression
    A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression Kazuhiro Ito, Sam Lim, Gaetano Caramori, Borja Cosio, K. Fan Chung, Ian M. Adcock*, and Peter J. Barnes Thoracic Medicine, Imperial College School of Science, Technology, and Medicine, National Heart and Lung Institute, Dovehouse Street, London SW3 6LY, United Kingdom Edited by Joseph A. Beavo, University of Washington School of Medicine, Seattle, WA, and approved May 1, 2002 (received for review October 18, 2001) The molecular mechanism for the anti-inflammatory action of low-dose theophylline gives a greater improvement in asthma theophylline is currently unknown, but low-dose theophylline is an control, measured as lung function, symptoms, and rescue ␤ effective add-on therapy to corticosteroids in controlling asthma. 2-agonist use, than that achieved by doubling the dose of Corticosteroids act, at least in part, by recruitment of histone inhaled corticosteroid (5, 14, 15). deacetylases (HDACs) to the site of active inflammatory gene The molecular mechanisms for the anti-inflammatory action transcription. They thereby inhibit the acetylation of core histones of theophylline are unclear. The bronchodilator action of the- that is necessary for inflammatory gene transcription. We show ophylline can be explained by the inhibition of phosphodiester- both in vitro and in vivo that low-dose theophylline enhances ases (PDEs) in airway smooth muscle, but this occurs at con- HDAC activity in epithelial cells and macrophages. This increased centrations of Ͼ50 ␮M (16). In addition, the common side HDAC activity is then available for corticosteroid recruitment and effects of theophylline, nausea and vomiting, are probably predicts a cooperative interaction between corticosteroids and because of PDE4 inhibition (13, 17).
    [Show full text]
  • Wo 2008/157205 A2
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date PCT (10) International Publication Number 24 December 2008 (24.12.2008) WO 2008/157205 A2 (51) International Patent Classification: David, W. [US/US]; 1028 Pinehurst Drive, Chapel Hill, A61K 31/352 (2006.01) A61P 13/00 (2006.01) NC 27517 (US). (21) International Application Number: (74) Agents: ERGENZINGER, Edward, R. et al; ALSTON PCT/US2008/066647 & BIRD LLP, Bank Of America Plaza, 101 South Tryon Street, Suite 4000, Charlotte, NC 28280-4000 (US). (22) International Filing Date: 12 June 2008 (12.06.2008) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (25) Filing Language: English AO, AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, (26) Publication Language: English EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, (30) Priority Data: LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, 60/944,182 15 June 2007 (15.06.2007) US MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, (71) Applicant (for all designated States except US): DUKE SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, UNIVERSITY [US/US]; 2812 Erwin Road, Suite 306, ZA, ZM, ZW Durham, NC 27705 (US).
    [Show full text]