Cytochrome P450 2J2 (CYP2J2) overexpression augments PPARα activation in vivo

Jessica A. Wray, Mary C. Sugden, Darryl, C. Zeldin, Gemma K. Greenwood, Laura M. Degraff, J. Alyce Bradbury, Mark J. Holness, Timothy D. Warner, and David Bishop-Bailey. William Harvey Research Institute, Barts & the London, Charterhouse Square, London EC1M 6BQ.

Peroxisome proliferator-activated receptor (PPAR)-α is a nuclear receptor involved in regulation of lipid metabolism (Bishop-Bailey, 2000). We have previously shown that products of CYP2J2, an abundant epoxygenase in human cardiovascular systems, activate PPARα in vitro (Wray et al, 2003). We have therefore, investigated whether CYP2J2 products activate PPAR a in vivo in CYP2J2 cardiac-specific transgenic mice.

Female cardiac-specific CYP2J2 transgenic mice (Seubert et al, 2004) and litter mate wild type controls (c57 black, 4-6months, 25-30g) were allowed food and water ad libitum or fasted for 24h. A nimals were then killed and hearts and kidneys removed. Expression of the PPAR a target gene, pyruvate dehydrogenase kinase (PDK)4, was compared to PDK1 by Western blot analysis (Sugden et al, 2001).

Upon fasting, PDK4 expression increased in wild type mice compared to fed a nimals (fig. 1). This response was augmented in the hearts (A) but not kidneys (B) of CYP2J2 transgenic mice. Fasting had no significant effect on the levels of PDK1 in either wild type or CYP2J2 transgenic mice (fold changes in PDK1: fed WT 1.0±0.02, fed 2J2 0.93±0.07, fasted WT 0.96±0.08, fasted 2J2, 1.04±0.14, n=4)

Figure 1. Cardiac-specific CYP2J2 over-expression augments fasting-induced (PPARα mediated) PDK4 expression in hearts (A), but not kidneys (B). Female wild type (WT) or cardiac-specific CYP2J2 transgenic (2J2) mice were either fed or fasted for 24h and PDK4 measured by Western blot. Data represents relative densitometry of protein compared to wild type fed controls (n=6 for all). * denotes p<0.05 by unpaired t-test.

Here we show that over-expression of CYP2J2 augments PPARα responses in vivo. CYP2J2 may well be a novel source of endogenous PPARα ligands in vivo.

Bishop-Bailey, D. (2000). Br. J. Pharmacol. 129 , 823-834
Wray, J.A., et al. (2003). Br. J. Pharmacol . 138, 169P.
Seubert, J. et al. (2004). Circ. Res. 95, 506-514.
Sugden, M.C., et al. (2001). Arch. Biochem. Biophys. 395, 246-252

This work was funded by grants from the British Heart Foundation (MCS, MJH; JAW, FS/04/075; DBB, BS/02/002), Diabetes UK (JKG), the William Harvey Research Foundation and the NIEHS division of Intramural Research (DCZ).