PPARγ Activation Prevents Sepsis-Related Cardiac Dysfunction and Mortality in Mice: Drosatos et al: PPARγ Treats Septic Cardiac Dysfunction

Impaired cardiac contractility contributes to the hypotension and increased mortality that occur with sepsis1. A possible cause of sepsis-mediated cardiac dysfunction is reduced energy production due in part to compromised fatty acid oxidation (FAO)2-5 and glucose catabolism3, 6. Thus, it is likely that sepsis compromises cardiac energy production, which might be the major cause of cardiac dysfunction. Alternatively, sepsis induces the production of inflammatory cytokines, such as tumor necrosis factor (TNF) α, interleukin (IL)-1 and IL-6, and these might directly alter heart function7-9. Intraperitoneal (i.p.) injection of lipopolysaccharide (LPS) has been extensively used to model many of the clinical features of sepsis, including elevated inflammation and cardiac dysfunction10. LPS leads to production of inflammatory cytokines7-9, 11 and also reduces cardiac energy utilization2, 3, 12. Nuclear receptors, particularly peroxisomal proliferator-activated receptors (PPARs), regulate cardiac FAO. The PPAR family consists of three members, PPARα, PPARδ and PPARγ. PPARα increases FA storage in triglycerides13 and FAO in heart14 and induces expression of peroxisomal and mitochondrial enzymes. Besides PPARα, cardiac FAO can be increased by activation of PPARγ15 or PPARδ16. Cardiomyocyte-specific overexpression of PPARα14 or PPARγ17 leads to cardiac lipid accumulation, an indication that lipid uptake exceeds FAO. PPARγ-coactivator-1 (PGC-1) α and β18 enhance FAO and mitochondrial biogenesis19. Both PPARα and PGC-1 mRNA levels are markedly reduced in the heart by LPS administration2, 3, 12, 20, while PPARγ is not affected2. Our group showed that maintenance of normal cardiac FAO via c-Jun-N-terminal kinase (JNK) inhibitor-mediated prevention of PPARα downregulation rescued cardiac function in septic mice despite elevated expression of cardiac inflammatory markers. In a similar context constitutive cardiac expression of PGC-1β prevented cardiac dysfunction that was caused by LPS-mediated sepsis3, an observation that was proposed to be due to improvement in cardiac FAO and attenuation of reactive oxygen species production. In the current study we show that constitutive cardiomyocyte-specific expression of PPARγ or systemic administration of the PPARγ agonist, rosiglitazone, increased cardiac FAO and prevented cardiac dysfunction in mice with LPS-induced sepsis, despite increased expression of cardiac inflammatory markers. In addition, we show that rosiglitazone-mediated activation of PPARγ prevents the loss of cardiac mitochondria that occurs in sepsis. Moreover, we show that restoration of cardiac FAO by rosiglitazone not only prevents but also treats LPS-induced heart dysfunction and improves survival. Thus the use of rosiglitazone is proposed as a potential treatment for septic cardiac dysfunction.