Abstract 13269: Activation of Pparγ Increases Energy Production and Prevents Cardiac Dysfunction in Sepsis
Sepsis leads to cardiac dysfunction and is associated with both inflammation and suppression of fatty acid oxidation (FAO). It remains unknown whether inflammation or reduced energy production is the major cause for cardiac dysfunction. We hypothesized that energy deprivation accounts for sepsis-related cardiac dysfunction. We used lipopolysaccharide (LPS) in C57BL/6 mice to induce cardiac dysfunction and reduce mRNA levels of genes required for cardiac FAO: Peroxisome proliferator activating receptor (PPAR)α, cluster of differentiation (CD)36, lipoprotein lipase (LpL), fatty acid transport protein (FATP), carnitine palmitoyl-transferase (Cpt)1, PPARγ coactivator (PGC)-1α and PGC-1β. Cardiac ATP and FAO were reduced (44% and 61%). In contrast, LPS did not induce cardiac dysfunction in mice with cardiomyocyte-specific expression of PPARγ (αMHC-PPARγ). Despite a 77% reduction in PPARα, the expression of FAO-associated genes, such as acyl-CoA oxidase (AOX), PGC-1α, PPARδ, Cpt1, uncoupling protein (UCP)2 and UCP3, increased (27-, 30-, 32-, 14-, 24- and 17-fold)as compared to saline-treated αMHC-PPARg mice. Similarly, cardiac FAO and ATP content were significantly increased (2.6 and 5-fold) in LPS-treated αMHC-PPARγ transgenic mice as compared to C57BL/6 mice that were treated with LPS. LPS increased inflammation-related gene expression; Interleukin (IL)-1α, IL-6 and tumor necrosis factor (TNF)α in control C57BL/6 (37-, 689- and 11-fold) and αMHC-PPARγ transgenic (23-, 288- and 13-fold) mice. Treatment of C57BL/6 mice with LPS and the PPARγ agonist, rosiglitazone [intraperitoneally (30mg/kg)], prevented cardiac dysfunction and increased FAO and relevant gene expression despite continued increases in IL-1α, IL-6 and TNFα mRNA levels. Thus, activation of PPARγ in LPS-treated mice increased cardiac FAO-associated gene expression, stabilized ATP content and prevented cardiac dysfunction despite development of cardiac inflammation and PPARα downregulation. (Funding: AHA #10POST4440032)
- © 2011 by American Heart Association, Inc.