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

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
• 2 Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators.  Nature. 1990;  347 645-650
• 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]
• 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
• 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
• 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
• 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
• 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
• 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
• 10 Hsueh WA, Bruemmer D. Peroxisome proliferator-activated receptor gamma: implications for cardiovascular disease.  Hypertension. 2004;  43 297-305
• 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
• 12 Jiang C, Ting AT, Seed B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines.  Nature. 1998;  391 82-86
• 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
• 14 Ahima RS, Flier JS. Adipose tissue as an endocrine organ.  Trends Endocrinol Metab. 2000;  11 327-332
• 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
• 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
• 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
• 18 Yudkin JS. Inflammation, obesity, and the metabolic syndrome.  Horm Metab Res. 2007;  39 707-709
• 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
• 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
• 21 Martich GD, Boujoukos AJ, Suffredini AF. Response of man to endotoxin.  Immunobiology. 1993;  187 403-416
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 33 Riva CE, Petrig B. Blue field entoptic phenomenon and blood velocity in the retinal capillaries.  J Opt Soc Am. 1980;  70 1234-1238
• 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
• 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
• 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
• 37 Zingarelli B, Cook JA. Peroxisome proliferator-activated receptor-gamma is a new therapeutic target in sepsis and inflammation.  Shock. 2005;  23 393-399
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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

Correspondence