Abstract 5380: Cardiac-specific Knock-out Of Ppardelta Brings Down Cardiac Metabolism And Alters Cardiac Gene Expression
Fatty acid oxidation is the primary energy source for the heart, and is regulated by peroxisome proliferator activated receptors (PPARs). Our Previous studies on cardiomyocyte-restricted knockout of PPARdelta mice had shown that PPARdelta is essential for the heart to maintain energy and lipid homeostasis. To further define the importance of PPARdelta in adult hearts, we assessed a tamoxifen inducible PPARdelta knockout line (TMPD), which was bred by crossing the alpha-MyHC driven Mer-Cre-Mer (TMCM) transgenic mice with the floxed PPARdelta mice. Treatment of tamoxifen in adult mice induced cardiomyocyte-restricted Cre release in TMCM mice and consequent cardiomyocyte-restricted knockout of PPARdelta in TMPD mice. Quantitative real time PCR (qPCR) and Western blot studies confirmed that TMPD mice exhibited remarkably decreased PPARdelta mRNA levels and protein levels (about 25% of that of controls) in their heart compared to those from controlled mice. High resolution echocardiographic measurement indicated left ventricular enlargement and cardiac dysfunction in TMPD mice after 3.5 months of tamoxifen-induced PPARdelta knockout (LVID-s: 2.23±0.10 vs 1.78±0.14 mm; LVAW-d: 0.81±0.02 vs 0.96±0.05 mm; LVAW-s 1.26±0.04 vs 1.50±0.11 mm; %EF: 70.21±1.60% vs 78.61±2.74%; n=8, p < 0.05). 14C-labelled substrate metabolic studies demonstrated that fatty acid oxidation in cardiomyocytes isolated from TMPD mice declined by about 40% (7.84±0.73 vs 12.99±1.62 nmol/min/million cells, n=6, p <0.01) relative to cardiomyocytes from TMCM mice, whereas no difference on glucose oxidation could be detected. Microarrays studies showed that In the 18,335 genes detected, 529 showed an increase of more than 1.5-fold in RNA expression and 534 showed a decrease of over 50%. The changes of interested genes were further verified by qPCR. Genes related to fatty acid oxidation showed no significant changes except ACADM and MCD L. However, genes related to fatty acid uptake such as CD36, FATP, ACC2 and LCPT deceased significantly. Thus, the loss of PPARdelta in the cardiomyocytes leads to dramatic shift of gene expression, and the decrease of fatty acid uptake induces heart dysfunction and defective fatty acid metabolism.