Nitric oxide and mitochondrial dysfunction as main effectors of cardiac dysfunction in endotoxemia

VICO TAMARA; MARCHINI TIMOTEO; FERRERO MARIANA; CORACH DANIEL; GELPI RICARDO J.; VANASCO VIRGINIA; CALABRÓ VALERIA; GINART SANTIAGO; D'ANNUNZIO VERONICA; ALVAREZ SILVIA; ADÁN AREÁN JUAN SANTIAGO; LORENZETTI MARIO A; GONZALEZ MAGLIO DANIEL; MAZO TAMARA; EVELSON PABLO

Ciudad Autonoma de Buenos Aires

Congreso; IV International Congress in Translational Medicine; 2018

Master Program in Biomedical Science- Universidad de Buenos Aires-Albert-Ludwigs University of Freiburg (Germany)

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Myocardial dysfunction is a known manifestation of this syndrome, although the mechanisms of how systemic inflammation could affect it remain still unknown. The magnitude of the inflammatory response is vital forresolving sepsis. The aim of this work was to elucidate the relationship between the severity of the systemic inflammatory response with cardiac mitochondrial function, and its impact on cardiac function. Female Sprague-Dawley rats received i.p. injection of LPS 0.5 mg/kg or LPS 8 mg/kg body wt or vehicle. After 6 h of treatment, NO and ROS production in blood cells were measured, pro-inflammatory cytokines levels were assessed in plasma and heart tissue, heart mitochondrial function was measured, and ventricular contractile reserve and lusitropic reserve were evaluated. NO levels in bloodstream were assessed by NO-Hb adduct by EPR; and nitrates/nitrites levels and NO increased by 5-fold in LPS 0.5 and by 11- fold in LPS 8. These results are accompanied by the increase in TNF-α and IL-6 levels in plasma. Also, polymorphonuclear cells (PMN) activation was evaluated byflow citometry. NO production in PMN increased by 42% and 60% in LPS 0.5 and LPS 8, while ROS production in PMN increased by 88% in LPS 0.5 and by 94% in LPS 8, respectively. LPS treatment induced mitochondrial dysfunction in the highest dose: ATP production decreased by 30%, mitochondrial membrane potential decrease by 18% as well as complex I activity. Mitochondrial H2O2 production increased by 40% and 59% in LPS 0.5 and LPS 8 doses (control: 0.128 ± 0.013 nmol/min-mg prot, p