Download PDF
Horm Metab Res 2008; 40(8): 549-555
DOI: 10.1055/s-2008-1076698
Humans, Clinical

© Georg Thieme Verlag KG Stuttgart · New York

Pioglitazone does not Affect Vascular or Inflammatory Responses after Endotoxemia in Humans

G. Schaller 1 , J. Kolodjaschna 1 , J. Pleiner 1 , F. Mittermayer 1 , S. Kapiotis 2 , L. Schmetterer 1 , 3 , M. Wolzt 1
  • 1Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
  • 2Department of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria
  • 3Department of Medical Physics, Medical University of Vienna, Vienna, Austria
Further Information

Publication History

received 27.06.2007

accepted 14.01.2008

Publication Date:
21 May 2008 (online)

Also available at
    Permissions and Reprints

Abstract

PPARγ agonists have been proposed to exert more than metabolic benefits, particularly by anti-inflammatory mechanisms. We hypothesized that pioglitazone might modulate inflammatory and vascular responses to lipopolysaccharide (LPS). In a placebo-controlled parallel-group study in 18 healthy male subjects, the E. coli endotoxin model of inflammation (20 IU/kg i. v.) was employed to test the effect of 60 mg pioglitazone over nine days on inflammatory cytokines. Macrovascular function and microvascular blood flow were assessed by brachial artery ultrasound and retinal blood flow parameters, respectively. Pioglitazone increased brachial artery diameter by 5.6% but had no effect on other outcome parameters under resting conditions. LPS increased cytokine levels to peak concentrations of 91.3±22.5 ng/ml (IL-6), 261.4±60.0 ng/ml (TNFα), and 524.5±15.3 ng/ml (VCAM-1). The endotoxin caused microvascular vasodilation and increased retinal white blood cell flux, while baseline brachial artery diameter remained unchanged. Pioglitazone had no effect on inflammatory cytokine or adhesion molecule release but mitigated LPS-induced hypotension (p<0.05). Neither brachial artery function nor microvascular blood flow was altered by pioglitazone. In conclusion, acute immune reactions to LPS are not affected by pioglitazone, which exerts subtle vascular effects alone and during endotoxemia. The anti-inflammatory properties of short-term pioglitazone to endotoxins in healthy subjects are therefore limited.

Key words

LPS - glitazones - inflammation - cytokines - vascular function

References

  • 1 Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma).  J Biol Chem. 1995;  270 12953-12956
    CrossrefPubMedGoogle Scholar
  • 2 Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators.  Nature. 1990;  347 645-650
    CrossrefPubMedGoogle Scholar
  • 3 Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.  N Engl J Med. 2007;  , [Epub ahead of print]
    PubMedGoogle Scholar
  • 4 Mittermayer F, Schaller G, Pleiner J, Krzyzanowska K, Kapiotis S, Roden M, Wolzt M. Rosiglitazone prevents free fatty acid-induced vas-cular endothelial dysfunction.  J Clin Endocrinol Metab. 2007;  92 2574-2580
    CrossrefPubMedGoogle Scholar
  • 5 Chawla A, Schwarz EJ, Dimaculangan DD, Lazar MA. Peroxisome proliferator-activated receptor (PPAR) gamma: adipose-predominant expression and induction early in adipocyte differentiation.  Endocrinology. 1994;  135 798-800
    CrossrefPubMedGoogle Scholar
  • 6 Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation.  Nature. 1998;  391 79-82
    CrossrefPubMedGoogle Scholar
  • 7 Calnek DS, Mazzella L, Roser S, Roman J, Hart CM. Peroxisome proliferator-activated receptor gamma ligands increase release of nitric oxide from endothelial cells.  Arterioscler Thromb Vasc Biol. 2003;  23 52-57
    CrossrefPubMedGoogle Scholar
  • 8 Law RE, Goetze S, Xi XP, Jackson S, Kawano Y, Demer L, Fishbein MC, Meehan WP, Hsueh WA. Expression and function of PPARgamma in rat and human vascular smooth muscle cells.  Circulation. 2000;  101 1311-1318
    CrossrefPubMedGoogle Scholar
  • 9 Takata Y, Kitami Y, Yang ZH, Nakamura M, Okura T, Hiwada K. Vascular inflammation is negatively autoregulated by interaction between CCAAT/enhancer-binding protein-delta and peroxisome proliferator-activated receptor-gamma.  Circ Res. 2002;  91 427-433
    CrossrefPubMedGoogle Scholar
  • 10 Hsueh WA, Bruemmer D. Peroxisome proliferator-activated receptor gamma: implications for cardiovascular disease.  Hypertension. 2004;  43 297-305
    CrossrefPubMedGoogle Scholar
  • 11 Artwohl M, Fürnsinn C, Waldhäusl W, Hölzenbein T, Rainer G, Freudenthaler A, Roden M, Baumgartner-Parzer SM. Thiazolidine-diones inhibit proliferation of microvascular and macrovascular cells by a PPARgamma-independent mechanism.  Diabetologia. 2005;  48 586-594
    CrossrefPubMedGoogle Scholar
  • 12 Jiang C, Ting AT, Seed B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines.  Nature. 1998;  391 82-86
    CrossrefPubMedGoogle Scholar
  • 13 Konukoglu D, Hatemi H, Bayer H, Bagriacik N. Relationship between serum concentrations of interleukin-6 and tumor necrosis factor alpha in female Turkish subjects with normal and impaired glucose tolerance.  Horm Metab Res. 2006;  38 34-37
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Ahima RS, Flier JS. Adipose tissue as an endocrine organ.  Trends Endocrinol Metab. 2000;  11 327-332
    PubMedGoogle Scholar
  • 15 Castell JV, Gomez-Lechon MJ, David M, Fabra R, Trullenque R, Heinrich PC. Acute-phase response of human hepatocytes: regulation of acute-phase protein synthesis by interleukin-6.  Hepatology. 1990;  12 1179-1186
    CrossrefPubMedGoogle Scholar
  • 16 Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance.  Science. 1993;  259 87-91
    CrossrefPubMedGoogle Scholar
  • 17 Rotter V, Nagaev I, Smith U. Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-alpha, overexpressed in human fat cells from insulin-resistant subjects.  J Biol Chem. 2003;  278 45777-45784
    CrossrefPubMedGoogle Scholar
  • 18 Yudkin JS. Inflammation, obesity, and the metabolic syndrome.  Horm Metab Res. 2007;  39 707-709
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Mohanty P, Aljada A, Ghanim H, Hofmeyer D, Tripathy D, Syed T, Al-Haddad W, Dhindsa S, Dandona P. Evidence for a potent antiinflammatory effect of rosiglitazone.  J Clin Endocrinol Metab. 2004;  89 2728-2735
    CrossrefPubMedGoogle Scholar
  • 20 Cominacini L, Garbin U, Pasini AF, Davoli A, Campagnola M, Rigoni A, Tosetti L, Lo Cascio V. The expression of adhesion molecules on endothelial cells is inhibited by troglitazone through its antioxidant activity.  Cell Adhes Commun. 1999;  7 223-231
    CrossrefPubMedGoogle Scholar
  • 21 Martich GD, Boujoukos AJ, Suffredini AF. Response of man to endotoxin.  Immunobiology. 1993;  187 403-416
    CrossrefPubMedGoogle Scholar
  • 22 Suffredini AF, Fromm RE, Parker MM, Brenner M, Kovacs JA, Wesley RA, Parrillo JE. The cardiovascular response of normal humans to the administration of endotoxin.  N Engl J Med. 1989;  321 280-287
    CrossrefPubMedGoogle Scholar
  • 23 Pleiner J, Mittermayer F, Schaller G, MacAllister RJ, Wolzt M. High doses of vitamin C reverse Escherichia coli endotoxin-induced hyporeactivity to acetylcholine in the human forearm.  Circulation. 2002;  106 1460-1464
    CrossrefPubMedGoogle Scholar
  • 24 Pleiner J, Mittermayer F, Schaller G, Marsik C, MacAllister RJ, Wolzt M. Inflammation-induced vasoconstrictor hyporeactivity is caused by oxidative stress.  J Am Coll Cardiol. 2003;  42 1656-1662
    CrossrefPubMedGoogle Scholar
  • 25 Li H, Ruan XZ, Powis SH, Fernando R, Mon WY, Wheeler DC, Moorhead JF, Varghese Z. EPA and DHA reduce LPS-induced inflammation responses in HK-2 cells: evidence for a PPAR-gamma-dependent mechanism.  Kidney Int. 2005;  67 867-874
    CrossrefPubMedGoogle Scholar
  • 26 Takano H, Nagai T, Asakawa M, Toyozaki T, Oka T, Komuro I, Saito T, Masuda Y. Peroxisome proliferator-activated receptor activators inhibit lipopolysaccharide-induced tumor necrosis factor-alpha expression in neonatal rat cardiac myocytes.  Circ Res. 2000;  87 596-602
    CrossrefPubMedGoogle Scholar
  • 27 Reynolds K, Novosad B, Hoffhines A, Gipson J, Johnson J, Peters J, Gonzalez F, Gimble J, Hill M. Pretreatment with troglitazone decreases lethality during endotoxemia in mice.  J Endotoxin Res. 2002;  8 307-314
    CrossrefPubMedGoogle Scholar
  • 28 Ohata M, Suzuki H, Sakamoto K, Hashimoto K, Nakajima H, Yamauchi M, Hokkyo K, Yamada H, Toda G. Pioglitazone prevents acute liver injury induced by ethanol and lipopolysaccharide through the suppression of tumor necrosis factor-alpha.  Alcohol Clin Exp Res. 2004;  28 139S-144S
    PubMedGoogle Scholar
  • 29 Zingarelli B, Sheehan M, Hake PW, O’Connor M, Denenberg A, Cook JA. Peroxisome proliferator activator receptor-gamma ligands, 15-deoxy-delta(12,14)-prostaglandin J2 and ciglitazone, reduce systemic inflammation in polymicrobial sepsis by modulation of signal transduction pathways.  J Immunol. 2003;  171 6827-6837
    CrossrefPubMedGoogle Scholar
  • 30 Wolzt M, Schmetterer L, Rheinberger A, Salomon A, Unfried C, Breiteneder H, Ehringer H, Eichler HG, Fercher AF. Comparison of non-invasive methods for the assessment of haemodynamic drug effects in healthy male and female volunteers: sex differences in cardiovascular responsiveness.  Br J Clin Pharmacol. 1995;  39 347-359
    CrossrefPubMedGoogle Scholar
  • 31 Dandona P, Nix D, Wilson MF, Aljada A, Love J, Assicot M, Bohuon C. Procalcitonin increase after endotoxin injection in normal subjects.  J Clin Endocrinol Metab. 1994;  79 1605-1608
    CrossrefPubMedGoogle Scholar
  • 32 Fuchsjäger-Mayrl G, Pleiner J, Wiesinger GF, Sieder AE, Quittan M, Nuhr MJ, Francesconi C, Seit HP, Francesconi M, Schmetterer L, Wolzt M. Exercise training improves vascular endothelial function in patients with type 1 diabetes.  Diabetes Care. 2002;  25 1795-1801
    CrossrefPubMedGoogle Scholar
  • 33 Riva CE, Petrig B. Blue field entoptic phenomenon and blood velocity in the retinal capillaries.  J Opt Soc Am. 1980;  70 1234-1238
    CrossrefPubMedGoogle Scholar
  • 34 Blum M, Bachmann K, Wintzer D, Riemer T, Vilser W, Strobel J. Noninvasive measurement of the Bayliss effect in retinal autoregulation.  Graefes Arch Clin Exp Ophthalmol. 1999;  237 296-300
    CrossrefPubMedGoogle Scholar
  • 35 Riva CE, Grunwald JE, Sinclair SH, Petrig BL. Blood velocity and volumetric flow rate in human retinal vessels.  Invest Ophthalmol Vis Sci. 1985;  26 1124-1132
    PubMedGoogle Scholar
  • 36 Kolodjaschna J, Berisha F, Lung S, Schaller G, Polska E, Jilma B, Wolzt M, Schmetterer L. LPS-induced microvascular leukocytosis can be assessed by blue-field entoptic phenomenon.  Am J Physiol Heart Circ Physiol. 2004;  287 H691-H694
    CrossrefPubMedGoogle Scholar
  • 37 Zingarelli B, Cook JA. Peroxisome proliferator-activated receptor-gamma is a new therapeutic target in sepsis and inflammation.  Shock. 2005;  23 393-399
    CrossrefPubMedGoogle Scholar
  • 38 Diep QN, El Mabrouk M, Cohn JS, Endemann D, Amiri F, Virdis A, Neves MF, Schiffrin EL. Structure, endothelial function, cell growth, and inflammation in blood vessels of angiotensin II-infused rats: role of peroxisome proliferator-activated receptor-gamma.  Circulation. 2002;  105 2296-2302
    CrossrefPubMedGoogle Scholar
  • 39 Sidhu JS, Cowan D, Kaski JC. Effects of rosiglitazone on endothelial function in men with coronary artery disease without diabetes mellitus.  Am J Cardiol. 2004;  94 151-156
    CrossrefPubMedGoogle Scholar
  • 40 Watson C, Whittaker S, Smith N, Vora AJ, Dumonde DC, Brown KA. IL-6 acts on endothelial cells to preferentially increase their adherence for lymphocytes.  Clin Exp Immunol. 1996;  105 112-119
    CrossrefPubMedGoogle Scholar
  • 41 Xia P, Gamble JR, Rye KA, Wang L, Hii CS, Cockerill P, Khew-Goodall Y, Bert AG, Barter PJ, Vadas MA. Tumor necrosis factor-alpha induces adhesion molecule expression through the sphingosine kinase pathway.  Proc Natl Acad Sci USA. 1998;  95 14196-14201
    CrossrefPubMedGoogle Scholar
  • 42 Pasceri V, Wu HD, Willerson JT, Yeh ET. Modulation of vascular inflammation in vitro and in vivo by peroxisome proliferator-activated receptor-gamma activators.  Circulation. 2000;  101 235-238
    CrossrefPubMedGoogle Scholar
  • 43 Thieringer R, Fenyk-Melody JE, Le Grand CB, Shelton BA, Detmers PA, Somers EP, Carbin L, Moller DE, Wright SD, Berger J. Activation of peroxisome proliferator-activated receptor gamma does not inhibit IL-6 or TNF-alpha responses of macrophages to lipopolysaccharide in vitro or in vivo.  J Immunol. 2000;  164 1046-1054
    CrossrefPubMedGoogle Scholar
  • 44 Jackson SM, Parhami F, Xi XP, Berliner JA, Hsueh WA, Law RE, Demer LL. Peroxisome proliferator-activated receptor activators target human endothelial cells to inhibit leukocyte-endothelial cell interaction.  Arterioscler Thromb Vasc Biol. 1999;  19 2094-2104
    CrossrefPubMedGoogle Scholar
  • 45 Castrillo A, Mojena M, Hortelano S, Bosca L. Peroxisome proliferator-activated receptor-gamma-independent inhibition of macrophage activation by the non-thiazolidinedione agonist L-796,449. Comparison with the effects of 15-deoxy-delta(12,14)-prostaglandin J(2).  J Biol Chem. 2001;  276 34082-34088
    CrossrefPubMedGoogle Scholar
  • 46 Sopasakis VR, Sandqvist M, Gustafson B, Hammarstedt A, Schmelz M, Yang X, Jansson PA, Smith U. High local concentrations and effects on differentiation implicate interleukin-6 as a paracrine regulator.  Obes Res. 2004;  12 454-460
    CrossrefPubMedGoogle Scholar
  • 47 Fujishima S, Ohya Y, Nakamura Y, Onaka U, Abe I, Fujishima M. Troglitazone, an insulin sensitizer, increases forearm blood flow in humans.  Am J Hypertens. 1998;  11 1134-1137
    CrossrefPubMedGoogle Scholar
  • 48 Buchanan TA, Meehan WP, Jeng YY, Yang D, Chan TM, Nadler JL, Scott S, Rude RK, Hsueh WA. Blood pressure lowering by pioglitazone. Evidence for a direct vascular effect.  J Clin Invest. 1995;  96 354-360
    CrossrefPubMedGoogle Scholar
  • 49 Zhang F, Sowers JR, Ram JL, Standley PR, Peuler JD. Effects of pioglitazone on calcium channels in vascular smooth muscle.  Hypertension. 1994;  24 170-175
    CrossrefPubMedGoogle Scholar
  • 50 Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine.  Chest. 1992;  101 1644-1655
    CrossrefPubMedGoogle Scholar
  • 51 Fullert S, Schneider F, Haak E, Rau H, Badenhoop K, Lubben G, Usadel KH, Konrad T. Effects of pioglitazone in nondiabetic patients with arterial hypertension: a double-blind, placebo-controlled study.  J Clin Endocrinol Metab. 2002;  87 5503-5506
    CrossrefPubMedGoogle Scholar
  • 52 Hetzel J, Balletshofer B, Rittig K, Walcher D, Kratzer W, Hombach V, Haring HU, Koenig W, Marx N. Rapid effects of rosiglitazone treatment on endothelial function and inflammatory biomarkers.  Arterioscler Thromb Vasc Biol. 2005;  25 1804-1809
    CrossrefPubMedGoogle Scholar
  • 53 Rudofsky Jr G, Reismann P, Grafe IA, Konrade I, Djuric Z, Tafel J, Buchbinder S, Zorn M, Humpert PM, Hamann A, Morcos M, Nawroth PP, Bierhaus A. Improved vascular function upon pioglitazone treatment in type 2 diabetes is not associated with changes in mononuclear NF-kappaB binding activity.  Horm Metab Res. 2007;  39 665-671
    Article in Thieme ConnectPubMedGoogle Scholar
  • 54 Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials.  JAMA. 2007;  298 1180-1188
    CrossrefPubMedGoogle Scholar
  • 55 Dandona P, Aljada A, Chaudhuri A, Bandyopadhyay A. The potential influence of inflammation and insulin resistance on the pathogenesis and treatment of atherosclerosis-related complications in type 2 diabetes.  J Clin Endocrinol Metab. 2003;  88 2422-2429
    Google Scholar

Correspondence

M. Wolzt

Department of Clinical Pharmacology

Allgemeines Krankenhaus Wien

Waehringer Guertel 18-20

1090 Vienna

Austria

Phone: +43/1/40400 29 81

Fax: +43/1/40400 29 98

Email: michael.wolzt@meduniwien.ac.at

      >