Impaired SIRT3 activity mediates cardiac dysfunction in endotoxemia by calpain-dependent disruption of ATP synthesis
Introduction
Septic shock is a major cause of death in critically ill patients that results from multi organ failure as a consequence of a dysregulated immunologic and inflammatory response to infection. 40% to 50% of patients suffering from septic shock develop myocardial dysfunction, and cardiac dysfunction in sepsis is associated with poor prognosis [1,2]. Of note, cardiomyocyte death is rarely observed in septic cardiomyopathy, and myocardial function recovers completely in patients surviving sepsis, indicating that septic cardiomyopathy may be understood as a condition of transient functional depression [2,3]. Increasing evidence suggests that various defects in mitochondrial function may contribute to cardiac dysfunction in sepsis, including impaired ATP synthesis, oxidative stress and opening of the mitochondrial permeability transition pore, however the underlying mechanisms leading to mitochondrial dysfunction remain poorly understood [4,5].
Sirtuins comprise a family of NAD+-dependent enzymes that modulate protein function by removal of a variety of posttranslational modifications from lysine residues. SIRT3 is primarily localized within mitochondria, represents the major protein deacetylase within mitochondria, and detoxifies ROS and increases mitochondrial ATP regeneration by activation of Manganese superoxide dismutase (MnSOD) and various energy metabolic enzymes [[6], [7], [8], [9], [10]]. In the heart, SIRT3 is highly expressed and is required to maintain mitochondrial energetics and cardiac contractility [7]. Lack of SIRT3 causes cardiac hypertrophy and accelerates the development of pressure overload-induced heart failure, whereas overexpression of SIRT3 protects from agonist-induced and pressure overload-induced cardiac hypertrophy [7,8,11]. Importantly, several cardiac pathologies are associated with cellular NAD+ depletion, which has been proposed to impair sirtuin activity and to contribute to disease pathology. For example, severe mitochondrial NAD+ depletion occurs during ischemia reperfusion, and normalization of NAD+ levels by administration of the NAD+ precursor, nicotinamide mononucleotide (NMN), reduced cardiac infarct size [12,13]. With regards to SIRT3, exogenous NAD treatment or treatment with NMN have been shown to reverse pathological hypertrophy and to attenuate heart failure in a variety of animal models in a SIRT3-dependent fashion [[14], [15], [16], [17]].
PARP1 is a NAD+-dependent DNA repair enzyme which competes with sirtuins for NAD+ and which is hyperactivated in many cardiac pathologies, including patients with sepsis-induced cardiac dysfunction [18]. Similarly, sepsis due to cecal ligation and puncture has been shown to activate PARP1 and to deplete NAD+ and ATP in rat hearts [19]. In the current study, we hypothesized that endotoxemia-induced myocardial PARP1 activation may deplete cardiac NAD+ levels, thereby impairing SIRT3 activity and causing mitochondrial and contractile dysfunction.
Section snippets
Animals
129S1J/SvlmJ (S1J129), Sirt3tm1.1Fwa (SIRT3−/−) and Parp1tm1Zqw (PARP1−/−) mice were purchased at Jackson Laboratory (Bar Harbor, ME). Homozygous PARP1−/−/SIRT3−/− double knockout mice were generated by crossing homozygous SIRT3−/− and PARP1−/− mice. Animals were housed in individually ventilated cages with 12 h light/dark cycles at 22 °C. Mice were fed a laboratory standard chow and water ad libitum. The study conforms to the Guide for the Care and Use of Laboratory Animals published by the US
Impaired myocardial SIRT3 activity in LPS-induced endotoxemia
10 week-old male wildtype (WT) mice were investigated 6 h following injection of 10 mg/kg LPS or saline. LPS-treated WT mice showed markedly increased plasma levels of interleukin-12 subunit p70 (IL-12p70), interleukin-6 (IL-6), monocyte chemoattractant protein 1 (MCP-1) and tumor necrosis factor α (TNF-α) compared to saline-treated WT mice (Fig. 1 A). These results are in agreement with the occurrence of a systemic inflammation compatible with an endotoxemic state in LPS-treated mice. Based on
Discussion
In the current study, we provide evidence for a novel mechanism underlying the development of endotoxemia-induced cardiomyopathy. Our results suggest that (1) impaired SIRT3 activity contributes significantly to cardiac dysfunction in endotoxemia, (2) impaired myocardial SIRT3 activity facilitates calpain-mediated cleavage of ATP5A1 and subsequent disruption of ATP synthesis, and (3) suppression of SIRT3-dependent pathways may be relevant in human septic cardiomyopathy. In addition, we show
Sources of funding
This study was supported by a DAAD PhD scholarship to M.C.C., and by a research grant of the Deutsche Forschungsgemeinschaft to H.B. (Bu2126/3-1).
Declaration of Competing Interest
The authors declare that they have no conflict of interest.
Acknowledgments
None.
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Equally contributed.