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Toxicologic Pathology, Vol. 27, No. 5, 545-552 (1999)
DOI: 10.1177/019262339902700508

Troglitazone-Induced Heart and Adipose Tissue Cell Proliferation in Mice

M.A. Breider

Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division of Warner-Lambert Co., Ann Arbor, Michigan 48105

A.W. Gough

Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division of Warner-Lambert Co., Ann Arbor, Michigan 48105

J.R. Haskins

Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division of Warner-Lambert Co., Ann Arbor, Michigan 48105

G. Sobocinski

Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division of Warner-Lambert Co., Ann Arbor, Michigan 48105

F.A. De La Iglesia

Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division of Warner-Lambert Co., Ann Arbor, Michigan 48105

Troglitazone, a thiazolidinedione, is a novel agent for the oral treatment of non-insulin-dependent (Type II) diabetes mellitus; it works by increasing cell sensitivity to available insulin. Previous studies have shown that rodents treated with high doses of troglitazone develop increased heart weight and increased interscapular brown fat. This study investigated cellular proliferation in heart and brown fat of troglitazone-treated mice as well as possible interactions with an angiotensin-converting enzyme inhibitor (quinipril). B6C3F1 female mice were treated daily with either vehicle control, 125 mg/kg quinipril, 1,200 mg/kg troglitazone, or troglitazone/quinipril combination per os for up to 14 days. Four days before necropsy, mice were dosed with bromodeoxyuridine (BrdU) using osmotic pumps. Cell proliferation in heart, brown fat, and retroperitoneal white fat was investigated by means of light microscopic anti-BrdU immunolabeling techniques. Immunoelectron microscopy was used to determine the cell phenotypes and cellular distribution of BrdU label in heart and brown fat. Treatment with troglitazone for 2 wk resulted in increased heart and brown fat weights but in decreased white fat weight. Combination treatment with troglitazone and quinipril also resulted in decreased white fat weight compared with controls. Histologically, brown fat adipocytes in troglitazone- and troglitazone/quinipril-treated mice had coalescent lipid vacuoles and increased eosinophilia of the cytoplasm. White fat adipocytes in troglitazone- and troglitazone/quinipril-treated mice had decreased cell size and increased cytoplasmic eosinophilia. BrdU labeling revealed increased cell proliferation in troglitazone-treated hearts after 1 wk but did not reveal increased cell proliferation in quinipril- or troglitazone/quinipril-treated animals. Brown fat BrdU labeling after 1 wk was increased in troglitazone- and troglitazone/quinipril-treated mice. Ultrastructural anti-BrdU immunogold labeling demonstrated that troglitazone-treated heart and brown fat had greater populations of BrdU-labeled cells that were identified as endothelial cells. These results demonstrated that troglitazone-induced increased cardiac weight in mice can be prevented by quinipril and that increased cardiac weight coincides with early increased endothelial cell proliferation.

Key Words: Quinipril • Accupril® • adipocyte • angiotensin-converting enzyme inhibitor • antidiabetic • brown adipose • cardiac • endothelial • troglitazone • Rezulin®

References

  • Adams M., Montague CT, Prins JB, Holder JC, Smith SA, Sanders L., Digby JE, Sewter CP, Lazar MA, and Chatterjee VK (1997). Activators of peroxisome proliferator-activated receptor gamma have depot-specific effects on human preadipocyte differentiation. J. Clin. Invest. 100: 3149-3153.[ISI][Medline] [Order article via Infotrieve]
  • Balligand JL, Kelly RA, and Smith TW (1997). Cardiac endothelium and tissue growth. Prog. Cardiovasc. Dis. 39: 351-360.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Berger J., Bailey P., Biswas C., Cullinan CA, Doebber TW, Hayes NS, Saperstein R., Smith RG, and Leibowitz MD (1996). Thiazolidinediones produce a conformational change in peroxisomal proliferator-activated receptor-gamma: Binding and activation correlate with antidiabetic actions in db/db mice. Endocrinology 137: 4189-4195.[Abstract]
  • Booz GW and Baker KM (1996). The role of the renin-angiotensin system in the pathophysiology of cardiac remodeling. Blood Press. Suppl. 2: 10-18.
  • Bukowiecki L., Collet AJ, Follea N., Guay G., and Jahjah L (1982). Brown adipose tissue hyperplasia: A fundamental mechanism of adaptation to cold and hyperphagia. Am. J. Physiol. 242: E353-359.[ISI][Medline] [Order article via Infotrieve]
  • Castellot JJ Jr, Karnovsky MJ, and Spiegelman BM (1982). Differentiation-dependent stimulation of neovascularization and endothelial cell chemotaxis by 3T3 adipocytes. Proc. Natl. Acad. Sci. USA 79: 5597-5601.[Abstract/Free Full Text]
  • Ciaraldi TP, Gilmore A., Olefsky JM, Goldberg M., and Heidenreich KA (1990). In vitro studies on the action of CS-045, a new antidiabetic agent. Metabolism 39: 1056-1062.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Delafontaine P. (1995). Insulin-like growth factor I and its binding proteins in the cardiovascular system. Cardiovasc. Res. 30: 825-834.[Free Full Text]
  • de la Iglesia FA, Herman JR, McGuire EJ, Gough AW, and Masuda H. (1998). Chronic toxicity study of the antidiabetic troglitazone in Wistar rats. Toxicol. Sci. 42: 50 (abstract).
  • Dubey RK, Zhang HY. Reddy SR, Boegehold MA, and Kotchen TA (1993). Pioglitazone attenuates hypertension and inhibits growth of renal arteriolar smooth muscle in rats. Am. J. Physiol. 265: R726-732.[ISI][Medline] [Order article via Infotrieve]
  • Dzau VJ (1994). Cell biology and genetics of angiotensin in cardiovascular disease. J. Hypertens. Suppl. 12: S3-10.
  • Foellmi Adams LA, Wyse BM, Herron D. Nedergaard J., and Kletzien RF (1996). Induction of uncoupling protein in brown adipose tissue. Synergy between norepinephrine and pioglitazone, an insulin-sensitizing agent. Biochem. Pharmacol. 52: 693-701.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Fujiwara T., Yoshioka S., Yoshioka T., Ushiyama I., and Horikoshi H. (1988). Characterization of new oral antidiabetic agent CS-045. Studies in KK and ob/ob mice and Zucker fatty rats. Diabetes 37: 1549-1558.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Ghazzi MN, Perez JE, Antonucci TK, Driscoll JH, Huang SM, Faja BW, and Whitcomb RW (1997). Cardiac and glycemic benefits of troglitazone treatment in NIDDM. The Troglitazone Study Group. Diabetes 46: 433-439.[CrossRef][Medline] [Order article via Infotrieve]
  • Graf K., Xi XP, Hsueh WA, and Law RE (1997). Troglitazone inhibits angiotensin II-induced DNA synthesis and migration in vascular smooth muscle cells. FEBS Lett. 400: 119-121.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Gralinski MR, Rowse PE, and Breider MA (1998). Effects of troglitazone and pioglitazone on cytokine-mediated endothelial cell proliferation in vitro. J. Cardiovasc. Pharmacol. 31: 909-913.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Herman JR, McGuire EJ, de la Iglesia FA, Walsh KM, and Masuda H. (1998). Carcinogenicity study of the antidiabetic troglitazone in Wistar rats. Toxicol. Sci. 42: 50 (abstract).
  • Herman JR, Metz AL, McGuire EJ, de la Iglesia FA, and Masuda H. (1997). Subchronic toxicity of the antidiabetic troglitazone in Wistar rats. Fundam. Appl. Toxicol. 36(1): 273 (abstract).[CrossRef]
  • Himms Hagen J. (1985). Brown adipose tissue metabolism and thermogenesis. Annu. Rev. Nutr. 5: 69-94.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Hudlicka O., Brown M., and Egginton S. (1992). Angiogenesis in skeletal and cardiac muscle. Physiol. Rev. 72: 369-417.[Free Full Text]
  • Ito T., Tanuma Y., Yamada M., and Yamamoto M. (1991). Morphological studies on brown adipose tissue in the bat and in humans of various ages. Arch. Histol. Cytol. 54: 1-39.[ISI][Medline] [Order article via Infotrieve]
  • Law RE, Meehan WP, Xi XP, Graf K., Wuthrich DA, Coats W., Faxon D., and Hsueh WA (1996). Troglitazone inhibits vascular smooth muscle cell growth and intimal hyperplasia. J. Clin. Invest. 98: 1897-1905.[ISI][Medline] [Order article via Infotrieve]
  • Lee MK, Miles PD, Khoursheed M., Gao KM, Moossa AR, and Olefsky JM (1994). Metabolic effects of troglitazone on fructose-induced insulin resistance in the rat. Diabetes 43: 1435-1439.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Lehmann JM, Moore LB, Smith Oliver TA, Wilkison WO, Willson TM, and Kliewer SA (1995). An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J. Biol. Chem. 270: 12953-12956.[Abstract/Free Full Text]
  • Levy AP, Levy NS, Loscalzo J., Calderone A., Takahashi N., Yeo KT, Koren G., Colucci WS, and Goldberg MA (1995). Regulation of vascular endothelial growth factor in cardiac myocytes. Circ. Res. 76: 758-766.[Abstract/Free Full Text]
  • McGuire EJ, Dethloff LA, Parker RF, de la Iglesia FA, Gough AW, and Masuda H. (1998). Carcinogenicity study of the antidiabetic troglitazone in B6C3F, mice. Toxicol. Sci. 42: 50 (abstract).
  • McGuire EJ, Dethloff LA, Walsh KM, de la Iglesia FA, and Masuda H. (1997). Subchronic toxicity of the antidiabetic troglitazone in B6C3F1 mice. Fundam. Appl. Toxicol. 36(1): 273 (abstract).[CrossRef]
  • Morikang E., Benson SC, Kurtz TW, and Pershadsingh HA (1997). Effects of thiazolidinediones on growth and differentiation of human aorta and coronary myocytes. Am. J. Hypertens. 10: 440-446.[ISI][Medline] [Order article via Infotrieve]
  • Murano K., Inoue Y., Emoto M., Kaku K. and Kaneko T. (1994). CS-045, a new oral antidiabetic agent, stimulates fructose-2,6-bisphosphate production in rat hepatocytes. Eur. J. Pharmacol. 254: 257-262.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Nag AC (1980). Study of non-muscle cells of the adult mammalian heart: A fine structural analysis and distribution. Cytobios. 28: 41-61.[ISI][Medline] [Order article via Infotrieve]
  • Nakano N., Moriguchi A., Morishita R., Kida I., Tomita N., Matsumoto K., Nakamura T., Higaki J., and Ogihara T. (1997). Role of angiotensin II in the regulation of a novel vascular modulator, hepatocyte growth factor (HGF), in experimental hypertensive rats. Hypertension 30: 1448-1454.[Abstract/Free Full Text]
  • Ogihara T., Rakugi H., Ikegami H., Mikami H., and Masuo K. (1995). Enhancement of insulin sensitivity by troglitazone lowers blood pressure in diabetic hypertensives. Am. J. Hypertens. 8: 316-320.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Okuno A., Tamemoto H., Tobe K., Ueki K., Mori Y., Iwamoto K., Umesono K., Akanuma Y., Fujiwara T., and Horikoshi H. (1998). Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats. J. Clin. Invest. 101: 1354-1361.[ISI][Medline] [Order article via Infotrieve]
  • Rothwell CE, Bleavins MR, McGuire EJ, de la Iglesia FA, and Masuda H. (1997). 52-Week oral toxicity study of troglitazone in cynomolgus monkeys. Fundam. Appl. Toxicol. 36(1): 273 (abstract).[CrossRef]
  • Rothwell NJ, Stock MJ, and Tedstone AE (1987). Effects of ciglitazone on energy balance, thermogenesis and brown fat activity in the rat. Mol. Cell Endocrinol. 51: 253-257.
  • Saku K., Zhang B., Ohta T., and Arakawa K. (1997). Troglitazone lowers blood pressure and enhances insulin sensitivity in Watanabe heritable hyperlipidemic rabbits. Am. J. Hypertens. 10: 1027-1033.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Schneider MD and Parker TG (1991). Cardiac growth factors. Prog. Growth Factor Res. 3: 1-26.[CrossRef][Medline] [Order article via Infotrieve]
  • Schwartz S., Raskin P., Fonseca V., and Graveline JF (1998). Effect of troglitazone in insulin-treated patients with type II diabetes mellitus. Troglitazone and Exogenous Insulin Study Group (see comments). N. Engl. J. Med. 338: 861-866.[Abstract/Free Full Text]
  • Sears IB, MacGinnitie MA, Kovacs LG, and Graves RA (1996). Differentiation-dependent expression of the brown adipocyte uncoupling protein gene: Regulation by peroxisome proliferator-activated receptor gamma. Mol. Cell Biol. 16: 3410-3419.[Abstract]
  • Shimabukuro M., Higa S., Shinzato T., Nagamine F., Komiya I., and Takasu N. (1996). Cardioprotective effects of troglitazone in streptozotocin-induced diabetic rats. Metabolism 45: 1168-1173.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Sironi AM, Vichi S., Gastaldelli A., Pecori N., Anichini R., Foot E., Seghieri G., and Ferrannini E. (1997). Effects of troglitazone on insulin action and cardiovascular risk factors in patients with non-insulin-dependent diabetes. Clin. Pharmacol. Ther. 62: 194-202.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Spencer CM and Markham A. (1997). Troglitazone. Drugs 54: 89-101.[ISI][Medline] [Order article via Infotrieve]
  • Tafuri SR (1996). Troglitazone enhances differentiation, basal glucose uptake, and Glut1 protein levels in 3T3-L1 adipocytes. Endocrinology 137: 4706-4712.[Abstract]
  • Tai Tac, Jennermann C., Brown KK, Oliver BB, MacGinnitie MA, Wilkison WO, Brown HR, Lehmann JM, Kliewer SA, and Morris DC (1996). Activation of the nuclear receptor peroxisome proliferator-activated receptor gamma promotes brown adipocyte differentiation. J. Biol. Chem. 271: 29909-29914.[Abstract/Free Full Text]
  • Thiedemann K. (1991). Left ventricular hypertrophy. In: Cardiovascular and Musculoskeletal Systems, TC Jones, U Mohr, and RD Hunt (eds). Springer-Verlag, New York, pp. 41-50.
  • Yamashita H., Kizaki T., Ookawara T., Sato Y., Yamamoto M., Ohira Y., and Ohno H. (1994). Is insulin-like growth factor I involved in brown adipose tissue enlargement? Life Sci. 55: 141-148.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Yamashita H., Sato Y., Kizaki T., Oh S., Nagasawa J., and Ohno H. (1994). Basic fibroblast growth factor (bFGF) contributes to the enlargement of brown adipose tissue during cold acclimation. Pflugers Arch. 428: 352-356.[CrossRef][ISI][Medline] [Order article via Infotrieve]

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