title: The antidiabetic agent rosiglitazone upregulates SERCA2 and enhances TNF-alpha- and LPS-induced NF-kappaB-dependent transcription and TNF-alpha-induced IL-6 secretion in ventricular myocytes.
abstract: Positive hemodynamic effects of the antidiabetic agent rosiglitazone on perfused whole hearts have recently been described, but the mechanisms regulating these effects are not well understood. This study reports the effects of rosiglitazone on calcium regulation in isolated neonatal rat ventricular myocytes by measurement of Ca2+ transient decay rates and SERCA2 gene expression, and shows that rosiglitazone enhances known cardioprotective signaling pathways. Myocyte treatment with 10 micromol/L rosiglitazone accelerated Ca2+ transient decay rates by approximately 30%, enhanced SERCA2 mRNA levels by approximately 1.5-fold and SERCA2 production by approximately 3-fold. Rosiglitazone treatment (1, 5, and 10 micromol/L) also led to a dose-dependent increase (approximately 1.2-1.5-fold) in SERCA2 promoter activity. Comparable levels of cardiac SERCA overexpression have been associated with physiologically relevant and compensatory effects in vivo. These data link thiazolidinedione-induced improvement in cardiac myocyte function to an upregulation of SERCA2 gene expression. Since NF-kappaB-dependent pathways, including the upregulation of IL-6 secretion, were shown to protect neonatal rat ventricular myocytes from apoptosis upon TNFalpha stimulation, additional experiments were designed to determine whether rosiglitazone enhances TNFalpha-induced NF-kappaB-dependent transcription and IL-6 secretion. Because the endotoxin stress response in ventricular myocytes involves the upregulation of TNFalpha, and the activation of NF-kappaB, the effects of rosiglitazone on lipopolysaccharide-induced NF-kappaB-dependent transcription were also investigated. Treatment of neonatal rat ventricular myocytes with 10 micromol/L rosiglitazone enhanced TNF-alpha- and lipopolysaccharide-induced NF-kappaB-dependent transcription by approximately 1.8- and approximately 1.4-fold respectively, and TNF-alpha-induced IL-6 secretion by n1.5-fold. Rosiglitazone had no significant effects on basal levels of NF-kappaB-dependent transcription and IL-6 secretion. Thus, cardioprotective effects of rosiglitazone may be partly mediated by NF-kappaB.
authors.affiliation: The Rees-Stealy Research Foundation Laboratory, San Diego, USA.
authors.forename: Rajanya D
authors.initials: RD
authors.lastname: Shah
authors.forename: Frank
authors.initials: F
authors.lastname: Gonzales
authors.forename: Edwin
authors.initials: E
authors.lastname: Golez
authors.forename: Danielle
authors.initials: D
authors.lastname: Augustin
authors.forename: Shawna
authors.initials: S
authors.lastname: Caudillo
authors.forename: Ami
authors.initials: A
authors.lastname: Abbott
authors.forename: John
authors.initials: J
authors.lastname: Morello
authors.forename: Patrick M
authors.initials: PM
authors.lastname: McDonough
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Paolini
authors.forename: Huda E
authors.initials: HE
authors.lastname: Shubeita
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D000252:Calcium-Transporting ATPases / Q000378:metabolism*; D002478:Cells, Cultured; D004790:Enzyme Induction / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008156:Luciferases / Q000378:metabolism; D032342:Muscle Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D045162:Thiazolidinediones / Q000494:pharmacology*; D051996:Transcription Factor RelA; D014158:Transcription, Genetic / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: C506948:Atp2a2 protein, rat; D007004:Hypoglycemic Agents; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D045162:Thiazolidinediones; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000077154:Rosiglitazone; D008156:Luciferases; D001616:beta-Galactosidase; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D002118:Calcium