title: Diuretics prevent thiazolidinedione-induced cardiac hypertrophy without compromising insulin-sensitizing effects in mice.
abstract: Much concern has arisen regarding critical adverse effects of thiazolidinediones (TZDs), including rosiglitazone and pioglitazone, on cardiac tissue. Although TZD-induced cardiac hypertrophy (CH) has been attributed to an increase in plasma volume or a change in cardiac nutrient preference, causative roles have not been established. To test the hypothesis that volume expansion directly mediates rosiglitazone-induced CH, mice were fed a high-fat diet with rosiglitazone, and cardiac and metabolic consequences were examined. Rosiglitazone treatment induced volume expansion and CH in wild-type and PPARγ heterozygous knockout (Pparg(+/-)) mice, but not in mice defective for ligand binding (Pparg(P465L/+)). Cotreatment with the diuretic furosemide in wild-type mice attenuated rosiglitazone-induced CH, hypertrophic gene reprogramming, cardiomyocyte apoptosis, hypertrophy-related signal activation, and left ventricular dysfunction. Similar changes were observed in mice treated with pioglitazone. The diuretics spironolactone and trichlormethiazide, but not amiloride, attenuated rosiglitazone effects on volume expansion and CH. Interestingly, expression of glucose and lipid metabolism genes in the heart was altered by rosiglitazone, but these changes were not attenuated by furosemide cotreatment. Importantly, rosiglitazone-mediated whole-body metabolic improvements were not affected by furosemide cotreatment. We conclude that releasing plasma volume reduces adverse effects of TZD-induced volume expansion and cardiac events without compromising TZD actions in metabolic switch in the heart and whole-body insulin sensitivity.
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan; Cardiovascular Research Center, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Cherng-Shyang
authors.initials: CS
authors.lastname: Chang
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University, Tainan, Taiwan; Research Center of Infectious Disease and Signaling, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Pei-Jane
authors.initials: PJ
authors.lastname: Tsai
authors.affiliation: Division of Nephrology, National Cheng Kung University Hospital, Tainan, Taiwan.
authors.forename: Junne-Ming
authors.initials: JM
authors.lastname: Sung
authors.affiliation: Division of Cardiology, National Cheng Kung University Hospital, Tainan, Taiwan; Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Ju-Yi
authors.initials: JY
authors.lastname: Chen
authors.affiliation: Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan; Division of Nephrology, Department of Internal Medicine, E-DA Hospital/I-Shou University, Kaohsiung, Taiwan.
authors.forename: Li-Chun
authors.initials: LC
authors.lastname: Ho
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, North Carolina.
authors.forename: Kumar
authors.initials: K
authors.lastname: Pandya
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, North Carolina.
authors.forename: Nobuyo
authors.initials: N
authors.lastname: Maeda
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan; Cardiovascular Research Center, National Cheng Kung University, Tainan, Taiwan; Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan. Electronic address: yaustsai@mail.ncku.edu.tw.
authors.forename: Yau-Sheng
authors.initials: YS
authors.lastname: Tsai
mesh_terms: D000818:Animals; D002306:Cardiac Volume / Q000187:drug effects; D006332:Cardiomegaly / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000517:prevention & control*; D004232:Diuretics / Q000494:pharmacology / Q000627:therapeutic use*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005665:Furosemide / Q000494:pharmacology / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000378:metabolism; D000077205:Pioglitazone; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013148:Spironolactone / Q000494:pharmacology / Q000627:therapeutic use; D045162:Thiazolidinediones / Q000009:adverse effects*; D014237:Trichlormethiazide / Q000494:pharmacology / Q000627:therapeutic use; D014463:Ultrasonography
chemical_list: D004232:Diuretics; D007328:Insulin; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D013148:Spironolactone; D005665:Furosemide; D048049:Extracellular Signal-Regulated MAP Kinases; D005947:Glucose; D014237:Trichlormethiazide; D000077205:Pioglitazone