Impaired SIRT3 activity mediates cardiac dysfunction in endotoxemia by calpain-dependent disruption of ATP synthesis

KOENGTES, CHRISTOPH; CIMOLAI, MARÍA CECILIA; PFEIL, KATHARINA; WOLF, DENNIS; MARCHINI, TIMOTEO; TARKHNISHVILL, ALEKSANDRE; HOFFMAN, MICHAEL; ODENING, KATJA; DIEHL, PHILIPP; VON ZUR MUHLEN, CONSTANTIN; ALVAREZ, SILVIA; BODE, CHRISTOPH; ZIRLIK, ANDREAS; BUGGER, HEIKO

JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY

ACADEMIC PRESS LTD-ELSEVIER SCIENCE LTD

Lugar: Amsterdam; Año: 2019 vol. 133 p. 138 - 147

0022-2828

Background: Sepsis-induced cardiomyopathy contributes to the high mortalityof septic shock in critically ill patients. Since the underlying mechanisms areincompletely understood, we hypothesized that sepsis-induced impairment of sirtuin 3 (SIRT3)activity contributes to the development of septic cardiomyopathy.Methods and Results: Treatment of mice with lipopolysaccharide (LPS) for 6 hours resulted inmyocardial NAD+ depletion and increased mitochondrial proteinacetylation, indicating impaired myocardial SIRT3 activity due to NAD+depletion. LPS treatment also resulted in impaired cardiac output in isolatedworking hearts, indicating endotoxemia-inducedcardiomyopathy. Maintaining normal myocardial NAD+ levels inLPS-treated mice by Poly(ADP-ribose)polymerase 1 (PARP1) deletion preventedcardiac dysfunction, whereas additional SIRT3 deficiency blunted thisbeneficial effect, indicating that impaired SIRT3 activity contributes tocardiac dysfunction in endotoxemia. Measurements of mitochondrial ATP synthesissuggest that LPS-induced contractile dysfunction may result from cardiac energydepletion due to impaired SIRT3 activity. Pharmacological inhibition ofmitochondrial calpains using MDL28170 normalized LPS-induced cleavage of theATP5A1 subunit of ATP synthase and normalized contractile dysfunction,suggesting that cardiac energy depletion may result from calpain-mediatedcleavage of ATP5A1. These beneficial effects were completely blunted by SIRT3deficiency. Finally, a gene setenrichment analysis of hearts of patients with septic, ischemic or dilatedcardiomyopathy revealed a sepsis-specific suppression of SIRT3 deacetylationtargets, including ATP5A1, indicatinga functional relevance of SIRT3-dependent pathways in human sepsis.Conclusions:Impaired SIRT3 activity may mediate cardiac dysfunction in endotoxemia byfacilitating calpain-mediated disruption of ATP synthesis, suggesting SIRT3activation as a potential therapeutic strategy to treat septic cardiomyopathy.