Mitochondrial bioenergetics links inflammation and cardiac contractility in endotoxemia

TAMARA ANTONELA VICO; MARIO ALEJANDRO LORENZETTI; MARIANA GARCÉS; VERÓNICA DANNUNZIO; PABLO EVELSON; SANTIAGO GINART; VALERIA CALABRÓ; TAMARA MAZO; DANIEL CORACH; SILVIA ALVAREZ; TIMOTEO MARCHINI; JUAN SANTIAGO ADÁN AREÁN; MARIANA CRISTINA FERRERO; RICARDO J. GELPI; VIRGINIA VANASCO

BASIC RESEARCH IN CARDIOLOGY

DR DIETRICH STEINKOPFF VERLAG

Año: 2019 p. 38 - 54

0300-8428

There is current awareness about the central role of mitochondrial dysfunction in the development of cardiac dysfunction in systemic inflammatory syndromes, especially in sepsis and endotoxemia. The aim of this work was to elucidate the mechanism that governs the link between the severity of the systemic inflammatory insult and mitochondrial function, analysing the consequences on heart function, particularly in cardiac contractile state. Female Sprague-Dawley rats were subjected to low-grade endotoxemia (i.p. injection LPS 0.5 mg kg-1 body weight) and severe endotoxemia (i.p. injection LPS 8 mg kg-1 body weight) for 6 h. Blood NO, as well as cardiac TNF-α and IL-1β mRNA, were found increased as the severity of the endotoxemia increases. Cardiac relaxation was altered only in severe endotoxemia, although contractile and lusitropic reserves were found impaired in both treatments in response to work-overload. Cardiac ultrastructure showed disorientation of myofibrillar structure in both endotoxemia degrees, but mitochondrial swelling and cristae disruption were only observed in severe endotoxemia. Mitochondrial ATP production, O2 consumption and mitochondrial inner membrane potential decreases were related to blood NO levels and mitochondrial protein nitration, leading to diminished ATP availability and impairment of contractile state. Co-treatment with the NOS inhibitor L-NAME or the administration of the NO scavenger c-PTIO leads to the observation that mitochondrial bioenergetics status depends on the degree of the inflammatory insult mainly determined by blood NO levels. Unravelling the mechanisms involved in the onset of sepsis and endotoxemia improves the interpretation of the pathology, and provides new horizons for novel therapeutic targets.