Abstract 1548: PPARgamma Independent Effects Of Rosiglitazone In The Perfused Mouse Heart
Background: The PPARγ agonist, Rosiglitazone (Rosig), a hypoglycemic agent used to treat type 2 diabetes, has effects that cannot be explained solely by activation of PPARγ. Rosig treatment has been reported to increase AMP activated protein kinase (AMPK) activity by increasing AMP. The hypothesis was tested that acute Rosig treatment increases AMP independently of PPARγ in the mouse heart.
Methods: Isolated isovolumic perfused hearts from cardiomyocyte-specific PPARγ-knockout (PPARγ −) mice, littermate controls (PPARγ+) and C57BL/6 mice were studied. High energy phosphates were measured using 31P-NMR spectroscopy and HPLC. The phosphorylation of (α Thr-172) of AMPK and ERK1/2 was measured with western blots.
Results: After stabilization 30 μM Rosig or vehicle was added to the perfusate. In C57BL/6, PPARγ+ and PPARγ − hearts 30 μM Rosig decreased myocardial phosphocreatine concentration ([PCr]) and [ATP]; following increases in total [AMP] and calculated free [AMP]; and Rosig also increased phosphorylation of AMPK and ERK1/2.
Conclusions: In the perfused mouse heart, acute administration of Rosig decreases [ATP] and [PCr] independently of PPARγ. This increased the free [AMP], which increased the phosphorylation of AMPK and AMPK activity. ERK phosphorylation also increase independently of PPARγ