Chemically synthesized Secoisolariciresinol diglucoside (LGM2605) improves mitochondrial function in cardiac myocytes and alleviates septic cardiomyopathy

Dimitra Kokkinaki, Matthew Hoffman, Charikleia Kalliora, Ioannis D. Kyriazis, Jennifer Maning, Anna Maria Lucchese, Santhanam Shanmughapriya, Dhanendra Tomar, Joon Young Park, Hong Wang, Xiao Feng Yang, Madesh Muniswamy, Anastasios Lymperopoulos, Walter J. Koch, Melpo Christofidou-Solomidou, Konstantinos Drosatos

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Sepsis is the overwhelming systemic immune response to infection, which can result in multiple organ dysfunction and septic shock. Myocardial dysfunction during sepsis is associated with advanced disease and significantly increased in-hospital mortality. Our group has shown that energetic failure and excess reactive oxygen species (ROS) generation constitute major components of myocardial dysfunction in sepsis. Because ROS production is central to cellular metabolic health, we tested if the synthetic anti-oxidant lignan secoisolariciresinol diglucoside (SDG; LGM2605) would alleviate septic cardiac dysfunction and investigated the underlying mechanism. Using the cecal ligation and puncture (CLP) mouse model of peritonitis-induced sepsis, we observed impairment of cardiac function beginning at 4 h post-CLP surgery. Treatment of mice with LGM2605 (100 mg/kg body weight, i.p.) 6 h post-CLP surgery reduced cardiac ROS accumulation and restored cardiac function. Assessment of mitochondrial respiration (Seahorse XF) in primary cardiomyocytes obtained from adult C57BL/6 mice that had undergone CLP and treatment with LGM2605 showed restored basal and maximal respiration, as well as preserved oxygen consumption rate (OCR) associated with spare capacity. Further analyses aiming to identify the cellular mechanisms that may account for improved cardiac function showed that LGM2605 restored mitochondria abundance, increased mitochondrial calcium uptake and preserved mitochondrial membrane potential. In addition to protecting against cardiac dysfunction, daily treatment with LGM2605 and antibiotic ertapenem (70 mg/kg) protected against CLP-associated mortality and reversed hypothermia when compared against mice receiving ertapenem and saline. Therefore, treatment of septic mice with LGM2605 emerges as a novel pharmacological approach that reduces cardiac ROS accumulation, protects cardiac mitochondrial function, alleviates cardiac dysfunction, and improves survival.

Original languageEnglish (US)
Pages (from-to)232-245
Number of pages14
JournalJournal of Molecular and Cellular Cardiology
Volume127
DOIs
StatePublished - Feb 1 2019
Externally publishedYes

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Cardiomyopathies
Punctures
Cardiac Myocytes
Ligation
Reactive Oxygen Species
Sepsis
Respiration
Smegmamorpha
Lignans
Mitochondrial Membrane Potential
Therapeutics
Septic Shock
Hospital Mortality
Hypothermia
Peritonitis
Inbred C57BL Mouse
Oxidants
Oxygen Consumption
Thoracic Surgery
Mitochondria

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Chemically synthesized Secoisolariciresinol diglucoside (LGM2605) improves mitochondrial function in cardiac myocytes and alleviates septic cardiomyopathy. / Kokkinaki, Dimitra; Hoffman, Matthew; Kalliora, Charikleia; Kyriazis, Ioannis D.; Maning, Jennifer; Lucchese, Anna Maria; Shanmughapriya, Santhanam; Tomar, Dhanendra; Park, Joon Young; Wang, Hong; Yang, Xiao Feng; Muniswamy, Madesh; Lymperopoulos, Anastasios; Koch, Walter J.; Christofidou-Solomidou, Melpo; Drosatos, Konstantinos.

In: Journal of Molecular and Cellular Cardiology, Vol. 127, 01.02.2019, p. 232-245.

Research output: Contribution to journalArticle

Kokkinaki, D, Hoffman, M, Kalliora, C, Kyriazis, ID, Maning, J, Lucchese, AM, Shanmughapriya, S, Tomar, D, Park, JY, Wang, H, Yang, XF, Muniswamy, M, Lymperopoulos, A, Koch, WJ, Christofidou-Solomidou, M & Drosatos, K 2019, 'Chemically synthesized Secoisolariciresinol diglucoside (LGM2605) improves mitochondrial function in cardiac myocytes and alleviates septic cardiomyopathy', Journal of Molecular and Cellular Cardiology, vol. 127, pp. 232-245. https://doi.org/10.1016/j.yjmcc.2018.12.016
Kokkinaki, Dimitra ; Hoffman, Matthew ; Kalliora, Charikleia ; Kyriazis, Ioannis D. ; Maning, Jennifer ; Lucchese, Anna Maria ; Shanmughapriya, Santhanam ; Tomar, Dhanendra ; Park, Joon Young ; Wang, Hong ; Yang, Xiao Feng ; Muniswamy, Madesh ; Lymperopoulos, Anastasios ; Koch, Walter J. ; Christofidou-Solomidou, Melpo ; Drosatos, Konstantinos. / Chemically synthesized Secoisolariciresinol diglucoside (LGM2605) improves mitochondrial function in cardiac myocytes and alleviates septic cardiomyopathy. In: Journal of Molecular and Cellular Cardiology. 2019 ; Vol. 127. pp. 232-245.
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AU - Kyriazis, Ioannis D.

AU - Maning, Jennifer

AU - Lucchese, Anna Maria

AU - Shanmughapriya, Santhanam

AU - Tomar, Dhanendra

AU - Park, Joon Young

AU - Wang, Hong

AU - Yang, Xiao Feng

AU - Muniswamy, Madesh

AU - Lymperopoulos, Anastasios

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AU - Christofidou-Solomidou, Melpo

AU - Drosatos, Konstantinos

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