Nonhematopoietic Peroxisome Proliferator-Activated Receptor-α Protects Against Cardiac Injury and Enhances Survival in Experimental Polymicrobial Sepsis

Objectives: Peroxisome proliferator-activated receptor-a is significantly down-regulated in circulating leukocytes from children with sepsis. Peroxisome proliferator-activated receptor-a null (Ppara(-/-)) mice have greater mortality than wild-type mice when subjected to sepsis by cecal ligation and puncture. We sought to characterize the role of peroxisome proliferator-activated receptor-a in sepsis and to identify the mechanism whereby peroxisome proliferator-activated receptor-a confers a survival advantage. Design: Prospective randomized preclinical study. Setting: Laboratory investigation. Subjects: Male C57Bl/6J and Ppara(-/-) mice (B6.129S4-Ppara(tm1Gonz)/J), aged 12-16 weeks. Interventions: Bone marrow chimeric mice were generated and subjected to cecal ligation and puncture. Survival was measured for 7 days. Separate groups of nontransplanted mice underwent cecal ligation and puncture and were euthanized 24 hours later for plasma and tissue analyses. Measurements and Main Results: Ppara(-/-) mice had dramatically reduced survival compared with wild-type mice irrespective of the peroxisome proliferator-activated receptor-a status of the bone marrow they received (3% vs 63%; p < 0.0001). No difference in survival was observed between Ppara(-/-) mice that received wild-type versus Ppara(-/-) marrow or in wild-type mice receiving wild-type versus Ppara(-/-) marrow. In septic, nontransplanted mice at 24 hours, Ppara(-/-) mice had elevated cardiac troponin levels compared with wild-type mice. Cardiac histologic injury scores were greater in Ppara(-/-) versus wild-type mice. Expression of transcription factors and enzymes related to fatty acid oxidation in the heart were profoundly down-regulated in both wild-type and Ppara(-/-) mice, but more so in the Ppara(-/-) mice. Conclusions: Peroxisome proliferator-activated receptor-a expression in nonhematopoietic tissues plays a critical role in determining clinical outcome in experimental polymicrobial sepsis and is more important to survival in sepsis than hematopoietic peroxisome proliferator-activated receptor-a expression. Cardiac injury due to inadequate energy production from fatty acid substrate is a probable mechanism of decreased survival in Ppara(-/-) mice. These results suggest that altered peroxisome proliferator-activated receptor-a-mediated cellular metabolism may play an important role in sepsis-related end-organ injury and dysfunction, especially in the heart.