Endotoxemia Engages the RhoA Kinase Pathway to Impair Cardiac Function By Altering Cytoskeleton, Mitochondrial Fission, and Autophagy

Preau, Sébastien; Delguste, Florian; Yu, Yongsheng; Rémy-Jouet, Isabelle; Richard, Vincent; Saulnier, F.; Boulanger, Éric; Nevière, Rémi

doi:10.1089/ars.2015.6421

Cited by 62 publications

(65 citation statements)

References 42 publications

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“…A new published study showed that myocardial aging is a T-cell-mediated phenomenon that heart-directed immune responses may spontaneously arise in the elderly [23]. Improvement of LPS-induced mitochondrial dysfunction by fasudil was attributed to inhibition of ROCK-dependent Drp1 phosphorylation and activation of autophagic processes [24]. Overall our data indicate the relationship between AMPK and autophagy response to LPS treatment in heart dysfunction.…”

Section: Discussionsupporting

confidence: 56%

The endotoxemia cardiac dysfunction is attenuated by AMPK/mTOR signaling pathway regulating autophagy

Zhang

Zhao

Quan

et al. 2017

Biochemical and Biophysical Research Communications

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AMP-activated protein kinase (AMPK), an enzyme that plays a role in cellular energy homeostasis, modulates myocardial signaling in the heart. Myocardial dysfunction is a common complication of sepsis. Autophagy is involved in the aging related cardiac dysfunction. However, the role of AMPK in sepsis-induced cardiotoxicity has yet to be clarified, especially in aging. In this study, we explored the role of AMPK in lipopolysaccharide (LPS)-induced myocardial dysfunction and elucidated the potential mechanisms of AMPK/mTOR pathway regulating autophagy in young and aged mice. We harvested cardiac tissues by intraperitoneal injection of LPS treatment. The results by echocardiography, pathology, contractile and intracellular Ca2+ property as well as western blot analysis revealed that LPS induced remarkable cardiac dysfunction and cardiotoxicity in mice hearts and cardiomyocytes, which were more seriously in the aged mice. Western blot analysis indicated that the underlying mechanisms included inhibition autophagy mediated by AMPK/mTOR activation. LPS overtly promoted the expression of AMPK upstream regulator PP2A and PP2Cα. Pharmacological activation of AMPK improved cardiac function and upregulated cardiac autophagy induced by LPS in the aged mice. Collectively, our findings suggest that upregulation of autophagy by administration of AMPK could attenuate LPS-induced cardiotoxicity, which enhances our knowledge to explore new drugs and strategies for combating cardiac dysfunction induced by sepsis.

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Section: Discussionsupporting

confidence: 56%

The endotoxemia cardiac dysfunction is attenuated by AMPK/mTOR signaling pathway regulating autophagy

Zhang

Zhao

Quan

et al. 2017

Biochemical and Biophysical Research Communications

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“…A related physiological process critical in energy maintenance that is activated by stress conditions, including infection, is autophagy. Recent studies highlight the contribution of proper autophagy regulation for cardiac function [41,42]. As we report here, pre-treatment with metformin protected the heart from the LPS-induced autophagy dysregulation, an additional indication for the effects of metformin on cardiac metabolism.…”

Section: Discussionsupporting

confidence: 65%

Metformin protects against infection-induced myocardial dysfunction

et al. 2016

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Background and Purpose Metformin administration is associated with myocardial protection during ischemia and/or reperfusion, possibly via inhibition of inflammatory responses in the heart. Exposure to pathogens, in addition to the activation of the immune system and the associated metabolic dysfunction, often results in compromised myocardial function. We examined whether metformin administration could maintain the normal myocardial function in experimental moderate Gram negative infection, induced by lipopolysaccharide (LPS) administration. Experimental Approach 129xC57BL/6 mice were divided into control groups that received either vehicle or a single intraperitoneal (i.p.) injection of low dose LPS (5 mg/kg body wt), and metformin treated groups that received either daily metformin (4 mg/kg/animal) i.p. injections for five days prior to LPS administration [Experiment 1], or a single metformin injection following same dose of LPS [Experiment 2]. Key Results LPS alone caused cardiac dysfunction, as confirmed by echocardiography, whereas metformin administration, either before or after LPS, rescued myocardial function. LPS caused marked reduction of the cardiac metabolism-related genes tested, including Prkaa2, Cpt1b, Ppargc1a and Ppargc1b; reduction of fatty acid oxidation, as reflected by the regulation of Ppara, Acaca and Acacb; increased glucose transport, as shown by Slc2a4 levels; reduction of ATP synthesis; significant increase of inflammatory markers, in particular IL6; and reduction of autophagy. Pretreatment with metformin normalized the levels of all these factors. Conclusions and Implications We show for the first time that metformin protects the myocardium from LPS-associated myocardial dysfunction mainly by supporting its metabolic activity and allowing efficient energy utilization. Metformin can be a potential cardioprotective agent in individuals susceptible to exposure to pathogens.

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“…Herein, the well-characterized NR8383 macrophages were used to investigate the effects of the HO-1/CO system on the levels of Fis1 and LPS-induced oxidative injury of cells and attempted to elucidate the possible mechanism of action. A number of studies indicated that abnormal mitochondrial fission was a determinant in the pathogenesis of sepsis (2,28,29). Fis1, a small molecule uniformly located in the mitochondrial outer membrane, was necessary for mitochondrial fission and removal of dysfunctional mitochondria (30,31).…”

Section: Discussionmentioning

confidence: 99%

Phosphatidylinositol 3‑kinase‑mediated HO‑1/CO represses Fis1 levels and alleviates lipopolysaccharide‑induced oxidative injury in alveolar macrophages

Shi

Zhang

et al. 2018

Exp Ther Med

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Abstract. Sepsis-related acute respiratory distress syndrome is characterized by marked oxidative stress and mitochondrial dysfunction lacking of specific therapy. Heme oxygenase (HO)-1 followed by endogenous carbon monoxide (CO) exerted a cytoprotective effect against multi-organ damage during sepsis. Additionally, the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway, which serves as an upstream regulator of HO-1, was associated with inflammation and oxidative stress. Therefore, the purpose of the present study was to investigate whether the PI3K/Akt pathway was involved in the effects of HO-1/CO on the expression of mitochondrial fission 1 protein (Fis1). In the present study, CO releasing molecule-2 (CORM2), as the exogenous source of CO, plus LY294002, as a specific PI3K inhibitor, were pre-incubated in lipopolysaccharide (LPS)-simulated rat NR8383 alveolar macrophages. The results demonstrated that CORM2 improved cell viability, inhibited tumor necrosis factor-α levels, malondialdehyde contents, while elevating interleukin-10 levels and superoxide dismutase activities. In addition, pretreatment with CORM2 suppressed the fragmentation of mitochondria, upregulated the expressions of phosphorylated-Akt and HO-1 but downregulated the levels of Fis1 mRNA and protein in LPS-exposed cells. However, pretreatment with LY294002 significantly inhibited the phosphorylation of Akt, decreased HO-1 levels, aggravated mitochondrial fragmentation, increased Fis1 mRNA and protein levels, and reversed the above protective effects of CORM2. Collectively, the results of the present study indicated that the PI3K/Akt pathway mediated the cytoprotective effects of HO-1/CO on the transcription and translational levels of Fis1, and alleviated LPS-induced oxidative injury in alveolar macrophages.

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Endotoxemia Engages the RhoA Kinase Pathway to Impair Cardiac Function By Altering Cytoskeleton, Mitochondrial Fission, and Autophagy

Abstract: Fasudil prevented LPS-induced heart oxidative stress, abnormal F-actin distribution, and oxidative phosphorylation, which concur to improve cardiac contractile and bioenergetic function. We suggest that fasudil may represent a valuable therapy for patients with sepsis.

Cited by 62 publications

References 42 publications

The endotoxemia cardiac dysfunction is attenuated by AMPK/mTOR signaling pathway regulating autophagy

The endotoxemia cardiac dysfunction is attenuated by AMPK/mTOR signaling pathway regulating autophagy

Metformin protects against infection-induced myocardial dysfunction

Phosphatidylinositol 3‑kinase‑mediated HO‑1/CO represses Fis1 levels and alleviates lipopolysaccharide‑induced oxidative injury in alveolar macrophages

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