PPAR-γ Activation Prevents Septic Cardiac Dysfunction via Inhibition of Apoptosis and Necroptosis

Sepsis-induced cardiac dysfunction remains one of the major causes of death in intensive care units. Overwhelmed inflammatory response and unrestrained cell death play critical roles in sepsis-induced cardiac dysfunction. Peroxisome proliferator-activated receptor- (PPAR-) gamma has been proven to be cardioprotective in sepsis. However, the mechanism of PPAR-gamma-mediated cardioprotection and its relationship with inflammation and cell death are unclear. We hypothesized that activation of PPAR-gamma by reducing cardiac inflammation, myocardial apoptosis, and necroptosis may prevent myocardial dysfunction in sepsis. Rats were subjected to cecal ligation and puncture (CLP) with or without PPAR-gamma agonist (rosiglitazone) or antagonist T0070907 (T007). After CLP, cardiac function was significantly depressed, which was associated with the destructed myocardium, upregulated proinflammatory cytokines, and increased apoptosis, necrosis, and necroptosis. This process is corresponded with decreased inhibitor kappa B (I kappa B alpha) and increased NF-kappa B, receptor-interacting protein kinase-1 (RIP1), RIP3, and mixed lineage kinase-like (MLKL) protein. Activation of PPAR-gamma by rosiglitazone pretreatment enhanced PPAR-gamma activity and prevented these changes, thereby improving the survival of septic rats. In contrast, inhibition of PPAR-gamma by T007 further exacerbated the condition, dropping the survival rate to nearly 0%. In conclusion, PPAR-gamma activation by reducing proinflammatory cytokines, apoptosis, and necroptosis in the myocardium prevents septic myocardial dysfunction.