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Basic Research in Cardiology

, 114:38 | Cite as

Mitochondrial bioenergetics links inflammation and cardiac contractility in endotoxemia

  • Tamara Antonela Vico
  • Timoteo Marchini
  • Santiago Ginart
  • Mario Alejandro Lorenzetti
  • Juan Santiago Adán Areán
  • Valeria Calabró
  • Mariana Garcés
  • Mariana Cristina Ferrero
  • Tamara Mazo
  • Verónica D’Annunzio
  • Ricardo J. Gelpi
  • Daniel Corach
  • Pablo Evelson
  • Virginia VanascoEmail author
  • Silvia AlvarezEmail author
Original Contribution

Abstract

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.

Keywords

Mitochondrial bioenergetics Cardiac dysfunction Systemic inflammation Endotoxemia Nitric oxide 

Abbreviations

ATP

Adenosine triphosphate

ADP

Adenosine diphosphate

BSA

Bovine serum albumin

c-PTIO

2-(4-Carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide potassium salt

DAF

4,5-Diaminofluorescein

DCF

2′,7′-Dichlorofluorescein

ISO

Isoproterenol

l-NAME

Nω-nitro-l-arginine methyl ester hydrochloride

LPS

Lipopolysaccharide

MM

Mitochondrial membranes

NADH

Nicotinamide adenine dinucleotide

NO

Nitric oxide

NOx

Nitrite/nitrate

ONOO

Peroxynitrite

PMN

Polymorphonuclear leukocytes

RCR

Respiratory control ratio

ROS

Reactive oxygen species

TNF-α

Tumor necrosis factor

Notes

Acknowledgements

The authors are grateful to Daniel Gonzalez Maglio for the helpful assistance with ELISA assays, to Elizabeth Robello for the assistance with EPR assays, and to Pablo La Padula for his helpful analysis of cardiac function.

Funding

This work was supported by research Grants from the Secretaría de Ciencia y Técnica, University of Buenos Aires [UBACYT2016 20020150100186BA]; Agencia Nacional de Promoción Científica y Tecnológica (ANPCYT) [PICT 2013-3227]; and Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) [PIP 11220120100321].

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

395_2019_745_MOESM1_ESM.pdf (226 kb)
Supplementary material 1 (PDF 54 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Tamara Antonela Vico
    • 1
    • 2
  • Timoteo Marchini
    • 1
    • 3
  • Santiago Ginart
    • 4
  • Mario Alejandro Lorenzetti
    • 5
  • Juan Santiago Adán Areán
    • 2
  • Valeria Calabró
    • 1
  • Mariana Garcés
    • 1
    • 3
  • Mariana Cristina Ferrero
    • 6
  • Tamara Mazo
    • 1
    • 7
  • Verónica D’Annunzio
    • 1
    • 7
  • Ricardo J. Gelpi
    • 1
    • 7
  • Daniel Corach
    • 4
  • Pablo Evelson
    • 1
    • 3
  • Virginia Vanasco
    • 1
    • 2
    Email author
  • Silvia Alvarez
    • 1
    • 2
    Email author
  1. 1.Instituto de Bioquímica y Medicina Molecular (IBIMOL), Facultad de Farmacia y BioquímicaUniversidad de Buenos Aires-CONICETBuenos AiresArgentina
  2. 2.Departamento de Química Analítica y Fisicoquímica, Facultad de Farmacia y Bioquímica, Cátedra de FisicoquímicaUniversidad de Buenos AiresBuenos AiresArgentina
  3. 3.Departamento de Química Analítica y Fisicoquímica, Facultad de Farmacia y Bioquímica, Cátedra de Química General e InorgánicaUniversidad de Buenos AiresBuenos AiresArgentina
  4. 4.Servicio de Huellas Digitales Genéticas, Facultad de Farmacia y BioquímicaUniversidad de Buenos AiresBuenos AiresArgentina
  5. 5.División Patología, Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas (IMIPP), CONICET-GCBAHospital de Niños Ricardo GutiérrezBuenos AiresArgentina
  6. 6.Instituto de Estudios de la Inmunidad Humoral (IDEHU), Facultad de Farmacia y BioquímicaUniversidad de Buenos Aires-CONICETBuenos AiresArgentina
  7. 7.Departamento de Patología, Instituto de Fisiopatología Cardiovascular, Facultad de MedicinaUniversidad de Buenos AiresBuenos AiresArgentina

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