PDF herunterladen
Horm Metab Res 2010; 42(9): 637-642
DOI: 10.1055/s-0030-1253373
Original Basic

© Georg Thieme Verlag KG Stuttgart · New York

The Decreased Expression of Peroxisome Proliferator-activated Receptors δ (PPARδ) is Reversed by Digoxin in the Heart of Diabetic Rats

S. C. Fan1 , B. C. Yu2 , Z. C. Chen3 , 4 , L. J. Chen2 , H. H. Chung2 , J. T. Cheng2 , 4
  • 1Department of Internal Medicine, Zhongxing Branch of Taipei City Hospital, Taipei City, Taiwan, R. O. C.
  • 2Institute of Basic Medical Sciences and Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan City, Taiwan, R. O. C.
  • 3Department of Cardiology, Chi-Mei Medical Center, Yong Kang City, Tainan Shen, Taiwan, R. O. C.
  • 4Department of Medical Research, Chi-Mei Medical Center, Yong Kang City, Tainan Shen, Taiwan, R. O. C.
Weitere Informationen

Publikationsverlauf

received 27.01.2010

accepted 31.03.2010

Publikationsdatum:
05. Mai 2010 (online)

Auch verfügbar auf
   Lizenzen und Reprints
Preview

Abstract

The present study is designed to investigate the role of peroxisome proliferator-activated receptors δ (PPARδ) in the action of digoxin in diabetic rats showing cardiac hypertrophy. We used Wistar rats to induce diabetes by injection of streptozotocin (STZ-rat) and examined the effect of digoxin on PPARδ expression in these hyperglycemic rats (STZ-rat) at 10 weeks later. We measured the changes of body weight, water intake, and food intake in three groups of age-matched rats; the vehicle treated normal control (Wistar rats), the vehicle treated STZ-rats, and the digoxin-treated STZ-rats. Cardiac output, heart rate, and blood pressure in addition to plasma insulin or glucose level were also determined. The mRNA and protein levels of PPARδ were measured using Northern and Western blotting, respectively. Cardiac output, heart rate, and blood pressure were markedly reduced while food intake, water intake, and blood glucose were raised in STZ-rats showing lower body weight and plasma insulin as compared with the vehicle-treated controls. After a 20-day of digoxin treatment, cardiac output was raised in STZ-rats but the diabetic parameters were not modified. The PPARδ expressions, both mRNA and protein, were markedly elevated in the hearts of STZ-rats by digoxin treatment. The related signals with PPARδ, such as carnitine palmitoyltransferase 1B (CPT1B), acetyl-coenzyme A, carboxylase alpha (ACC1), fatty acid synthase (FAS), and troponin I, were also raised. The increase of cardiac output by digoxin was reversed by the combined treatment with PPARδ antagonist GSK0660. Thus, we suggest a new finding that PPARδ is involved in digoxin induced cardiac inrotropic action.

Key words

digoxin - cardiac output - PPARδ - heart - diabetic rat

References

  • 1 Saini-Chohan HK, Hatch GM. Biological actions and metabolism of currently used pharmacological agents for the treatment of congestive heart failure.  Curr Drug Metab. 2009;  10 206-219
    Suche in Google Scholar
  • 2 Besch Jr HR, Watanabe AM. The positive inotropic effect of digitoxin: independence from sodium accumulation.  J Pharmacol Exp Ther. 1978;  207 958-965
    Suche in Google Scholar
  • 3 Pervaiz MH, Dickinson MG, Yamani M. Is digoxin a drug of the past?.  Cleve Clin J Med. 2006;  73 821-824 826, 829–832 and passim
    Suche in Google Scholar
  • 4 van Veldhuisen DJ, Man in ’ t Veld AJ, Dunselman PH, Lok DJ, Dohmen HJ, Poortermans JC, Withagen AJ, Pasteuning WH, Brouwer J, Lie KI. Doubleblind placebo-controlled study of ibopamine and digoxin in patients with mild to moderate heart failure: results of the Dutch Ibopamine Multicenter Trial (DIMT).  J Am Coll Cardiol. 1993;  22 1564-1573
    Suche in Google Scholar
  • 5 Ahmed A, Pitt B, Rahimtoola SH, Waagstein F, White M, Love TE, Braunwald E. Effects of digoxin at low serum concentrations on mortality and hospitalization in heart failure: a propensity-matched study of the DIG trial.  Int J Cardiol. 2008;  123 138-146
    Suche in Google Scholar
  • 6 Ohtsuki I, Morimoto S. Troponin: regulatory function and disorders.  Biochem Biophys Res Commun. 2008;  369 62-73
    Suche in Google Scholar
  • 7 Metzger JM, Westfall MV. Covalent and noncovalent modification of thin filament action: the essential role of troponin in cardiac muscle regulation.  Circ Res. 2004;  94 146-158
    Suche in Google Scholar
  • 8 Layland J, Solaro RJ, Shah AM. Regulation of cardiac contractile function by troponin I phosphorylation.  Cardiovasc Res. 2005;  66 12-21
    Suche in Google Scholar
  • 9 Bootman MD, Berridge MJ. The elemental principles of calcium signaling.  Cell. 1995;  83 675-678
    Suche in Google Scholar
  • 10 Yang Q, Li Y. Roles of PPARs on regulating myocardial energy and lipid homeostasis.  J Mol Med. 2007;  85 697-706
    Suche in Google Scholar
  • 11 Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators.  Nature. 1990;  347 645-650
    Suche in Google Scholar
  • 12 Cheng L, Ding G, Qin Q, Huang Y, Lewis W, He N, Evans RM, Schneider MD, Brako FA, Xiao Y, Chen YE, Yang Q. Cardiomyocyte-restricted peroxisome proliferator-activated receptor-delta deletion perturbs myocardial fatty acid oxidation and leads to cardiomyopathy.  Nat Med. 2004;  10 1245-1250
    Suche in Google Scholar
  • 13 Cheng L, Ding G, Qin Q, Xiao Y, Woods D, Chen YE, Yang Q. Peroxisome proliferator-activated receptor deltam activates fatty acid oxidation in cultured neonatal and adult cardiomyocytes.  Biochem Biophys Res Commun. 2004;  313 277-286
    Suche in Google Scholar
  • 14 Barish GD, Narkar VA, Evans RM. PPAR delta: a dagger in the heart of the metabolic syndrome.  J Clin Invest. 2006;  116 590-597
    Suche in Google Scholar
  • 15 Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: the Framingham study.  Am J Cardiol. 1974;  34 29-34
    Suche in Google Scholar
  • 16 Kannel WB, McGee DL. Diabetes and cardiovascular disease.  The Framingham study. J AMA. 1979;  241 2035-2038
    Suche in Google Scholar
  • 17 Malmberg K, Ryden L. Myocardial infarction in patients with diabetes mellitus.  Eur Heart J. 1988;  9 259-264
    Suche in Google Scholar
  • 18 Herlitz J, Malmberg K, Karlson BW, Ryden L, Hjalmarson A. Mortality and morbidity during a five-year follow-up of diabetics with myocardial infarction.  Acta Med Scand. 1988;  224 31-38
    Suche in Google Scholar
  • 19 Poornima IG, Parikh P, Shannon RP. Diabetic cardiomyopathy: the search for a unifying hypothesis.  Circ Res. 2006;  98 596-605
    Suche in Google Scholar
  • 20 An D, Rodrigues B. Role of changes in cardiac metabolism in development of diabetic cardiomyopathy.  Am J Physiol Heart Circ Physiol. 2006;  291 H1489-H1506
    Suche in Google Scholar
  • 21 Yu BC, Chang CK, Ou HY, Cheng KC, Cheng JT. Decrease of peroxisome proliferator-activated receptor delta expression in cardiomyopathy of streptozotocin-induced diabetic rats.  Cardiovasc Res. 2008;  80 78-87
    Suche in Google Scholar
  • 22 Fein FS, Kornstein LB, Strobeck JE, Capasso JM, Sonnenblick EH. Altered myocardial mechanics in diabetic rats.  Circ Res. 1980;  47 922-933
    Suche in Google Scholar
  • 23 Fein FS, Strobeck JE, Malhotra A, Scheuer J, Sonnenblick EH. Reversibility of diabetic cardiomyopathy with insulin in rats.  Circ Res. 1981;  49 1251-1261
    Suche in Google Scholar
  • 24 Shearer BG, Steger DJ, Way JM, Stanley TB, Lobe DC, Grillot DA, Iannone MA, Lazar MA, Willson TM, Billin AN. Identifi cation and characterization of a selective peroxisome proliferator-activated receptor beta/ delta (NR1C2) antagonist.  Mol Endocrinol. 2008;  22 523-529
    Suche in Google Scholar
  • 25 Dimopoulos N, Watson M, Green C, Hundal HS. The PPARdelta agonist, GW501516, promotes fatty acid oxidation but has no direct effect on glucose utilisation or insulin sensitivity in rat L6 skeletal muscle cells.  FEBS Lett. 2007;  581 4743-4748
    Suche in Google Scholar
  • 26 Tanaka T, Yamamoto J, Iwasaki S, Asaba H, Hamura H, Ikeda Y, Watanabe M, Magoori K, Ioka RX, Tachibana K, Watanabe Y, Uchiyama Y, Sumi K, Iguchi H, Ito S, Doi T, Hamakubo T, Naito M, Auwerx J, Yanagisawa M, Kodama T, Sakai J. Activation of peroxisome proliferator-activated receptor delta induces fatty acid beta-oxidation in skeletal muscle and attenuates metabolic syndrome.  Proc Natl Acadm Sci USA. 2003;  100 15924-15929
    Suche in Google Scholar
  • 27 Dressel U, Allen TL, Pippal JB, Rohde PR, Lau P, Muscat GE. The peroxisome proliferatoractivated receptor beta/delta agonist, GW501516, regulates the expression of genes involved in lipid catabolism and energy uncoupling in skeletal muscle cells.  Mol Endocrinol. 2003;  17 2477-2493
    Suche in Google Scholar
  • 28 Kobayashi T, Jin L, de Tombe PP. Cardiac thin filament regulation.  Pfl ugers Arch. 2008;  457 37-46
    Suche in Google Scholar
  • 29 Liu X, Takeda N, Dhalla NS. Troponin I phosphorylation in heart homogenate from diabetic rat.  Biochim Biophys Acta. 1996;  1316 78-84
    Suche in Google Scholar
  • 30 Messer AE, Jacques AM, Marston SB. Troponin phosphorylation and regulatory function in human heart muscle: dephosphorylation of Ser23/24 on troponin I could account for the contractile defect in end-stage heart failure.  J Mol Cell Cardiol. 2007;  42 247-259
    Suche in Google Scholar
  • 31 Ayaz-Guner S, Zhang J, Li L, Walker JW, Ge Y. In vivo phosphorylation site mapping in mouse cardiac troponin I by high resolution top-down electron capture dissociation mass spectrometry: Ser22/23 are the only sites basally phosphorylated.  Biochemistry. 2009;  48 8161-8170
    Suche in Google Scholar
  • 32 MacGowan GA, Evans C, Hu TC, Debrah D, Mullet S, Chen HH, McTiernan CF, Stewart AF, Koretsky AP, Shroff SG. Troponin I protein kinase C phosphorylation sites and ventricular function.  Cardiovasc Res. 2004;  63 245-255
    Suche in Google Scholar
  • 33 Tate CA, Hyek MF, Taffet GE. The role of calcium in the energetics of contracting skeletal muscle.  Sports Med. 1991;  12 208-217
    Suche in Google Scholar
  • 34 Li L, Desantiago J, Chu G, Kranias EG, Bers DM. Phosphorylation of phospholamban and troponin I in beta-adrenergic-induced acceleration of cardiac relaxation.  Am J Physiol Heart Circ Physiol. 2000;  278 H769-H779
    Suche in Google Scholar
  • 35 Pi Y, Kemnitz KR, Zhang D, Kranias EG, Walker JW. Phosphorylation of troponin I controls cardiac twitch dynamics: evidence from phosphorylation site mutants expressed on a troponin I-null background in mice.  Circ Res. 2002;  90 649-656
    Suche in Google Scholar

Correspondence

Prof. J. T. Cheng

Department of Medical

Research

Chi-Mei Medical Center

Yong Kang City

Taiwan 70301

R. O. C.

Telefon: +886/6/331 8516

Fax: +886/6/238 6548

eMail: m980103@mail.chimei.org.tw