The Antidiabetic Agent Rosiglitazone Upregulates SERCA2 and Enhances TNF-α- and LPS-Induced NF-κB-Dependent Transcription and TNF-α- Induced IL-6 Secretion in Ventricular Myocytes

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 μmol/ L rosiglitazone accelerated Ca2+ transient decay rates by ~30%, enhanced SERCA2 mRNA levels by ~1.5fold and SERCA2 production by ~3-fold. Rosiglitazone treatment (1, 5, and 10 μmol/L) also led to a dosedependent increase (~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-κB-dependent pathways, including the upregulation of IL-6 secretion, were shown to protect neonatal rat ventricular myocytes from apoptosis upon TNF-α stimulation, additional experiments were designed to determine whether rosiglitazone enhances TNF-α-induced NF-κB-dependent transcription and IL-6 secretion. Because the endotoxin stress response in ventricular myocytes involves the upregulation of TNF-α, and the activation of NF-κB, the effects of rosiglitazone on lipopolysaccharide-induced NF-κB-dependent transcription were also investigated. Treatment of neonatal rat ventricular myocytes with 10 μmol/L rosiglitazone enhanced TNF-αand lipopolysaccharide-induced NF-κB-dependent transcription by ~1.8and ~1.4-fold respectively, and TNF-αinduced IL-6 secretion by ~1.5-fold. Rosiglitazone had no significant effects on basal levels of NF-κBdependent transcription and IL-6 secretion. Thus, cardioprotective effects of rosiglitazone may be partly mediated by NF-κB.