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Activation of liver X receptor improves viability of adipose-derived mesenchymal stem cells to attenuate myocardial ischemia injury through TLR4/NF-?B and Keap-1/Nrf-2 signaling pathways.

ABSTRACT: Clinical application of cellular therapy for cardiac regeneration is significantly hampered by the low retention of engrafted cells, mainly attributable to the poor microenvironment dominated by inflammation and oxidative stress in the host's infarcted myocardium. This study aims at investigating whether liver X receptor (LXR) agonist T0901317 will improve survival of adipose-derived mesenchymal stem cells (AD-MSCs) after transplantation into infarcted hearts.Noninvasive in vivo bioluminescence imaging and histological staining showed that LXR agonist T0901317 improved the retention and survival of intramyocardially injected AD-MSCs. Moreover, combined therapy of LXR agonist and AD-MSCs inhibited host cardiomyocyte apoptosis, reduced fibrosis, and improved cardiac function, while it concomitantly decreased inflammatory cytokines (e.g., tumor necrosis factor-? and interleukin-6) and increased growth factor (e.g., vascular endothelial growth factor and basic fibroblast growth factor) expression in infarct myocardium. To reveal possible mechanisms, AD-MSCs were subjected to hypoxia/serum deprivation (H/SD) injury to simulate ischemic conditions in vivo. The LXR agonist (10(-7) mM) improved AD-MSC survival under H/SD condition. Western blot revealed that the LXR agonist reduced TLR4, TRAF-6, and MyD88 protein expression, inhibited I?B? phosphorylation and NF-?B-p65 nuclear translocation, which resulted in accelerated Keap-1 protein degradation, enhanced Nrf-2 nuclear translocation, and increased HO-1 protein expression.LXR agonist can enhance the functional survival of transplanted AD-MSCs in infarcted myocardium, at least partially, via modulation of the TLR4/NF-?B and Keap-1/Nrf-2 signaling pathways. Moreover, combined therapy of LXR agonist and AD-MSCs has a synergetic effect on cardiac repair and functional improvement after infarction.

SUBMITTER: Wang Y

PROVIDER: S-EPMC4245883 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Activation of liver X receptor improves viability of adipose-derived mesenchymal stem cells to attenuate myocardial ischemia injury through TLR4/NF-κB and Keap-1/Nrf-2 signaling pathways.

Wang Yabin Y Li Chunhong C Cheng Kang K Zhang Ran R Narsinh Kazim K Li Shuang S Li Xiujuan X Qin Xing X Zhang Rongqing R Li Congye C Su Tao T Chen Jiangwei J Cao Feng F

Antioxidants & redox signaling 20140731 18

<h4>Aims</h4>Clinical application of cellular therapy for cardiac regeneration is significantly hampered by the low retention of engrafted cells, mainly attributable to the poor microenvironment dominated by inflammation and oxidative stress in the host's infarcted myocardium. This study aims at investigating whether liver X receptor (LXR) agonist T0901317 will improve survival of adipose-derived mesenchymal stem cells (AD-MSCs) after transplantation into infarcted hearts.<h4>Results</h4>Noninva ...[more]

PMID: 24915051

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Project description:BACKGROUND:Neuroinflammation is the response of the central nervous system to events that interfere with tissue homeostasis and represents a common denominator in virtually all neurological diseases. Activation of microglia, the principal immune effector cells of the brain, contributes to neuronal injury by release of neurotoxic products. Toll-like receptor 4 (TLR4), expressed on the surface of microglia, plays an important role in mediating lipopolysaccharide (LPS)-induced microglia activation and inflammatory responses. We have previously shown that curcumin and some of its analogues harboring an ?,?-unsaturated 1,3-diketone moiety, able to coordinate the magnesium ion, can interfere with LPS-mediated TLR4-myeloid differentiation protein-2 (MD-2) signaling. Fluoroquinolone (FQ) antibiotics are compounds that contain a keto-carbonyl group that binds divalent ions, including magnesium. In addition to their antimicrobial activity, FQs are endowed with immunomodulatory properties, but the mechanism underlying their anti-inflammatory activity remains to be defined. The aim of the current study was to elucidate the molecular mechanism of these compounds in the TLR4/NF-?B inflammatory signaling pathway. METHODS:The putative binding mode of five FQs [ciprofloxacin (CPFX), levofloxacin (LVFX), moxifloxacin, ofloxacin, and delafloxacin] to TLR4-MD-2 was determined using molecular docking simulations. The effect of CPFX and LVFX on LPS-induced release of IL-1? and TNF-? and NF-?B activation was investigated in primary microglia by ELISA and fluorescence staining. The interaction of CPFX and LVFX with TLR4-MD-2 complex was assessed by immunoprecipitation followed by Western blotting using Ba/F3 cells. RESULTS:CPFX and LVFX bound to the hydrophobic region of the MD-2 pocket and inhibited LPS-induced secretion of pro-inflammatory cytokines and activation of NF-?B in primary microglia. Furthermore, these FQs diminished the binding of LPS to TLR4-MD-2 complex and decreased the resulting TLR4-MD-2 dimerization in Ba/F3 cells. CONCLUSIONS:These results provide new insight into the mechanism of the anti-inflammatory activity of CPFX and LVFX, which involves, at least in part, the activation of TLR4/NF-?B signaling pathway. Our findings might facilitate the development of new molecules directed at the TLR4-MD-2 complex, a potential key target for controlling neuroinflammation.

Dataset Information

Activation of liver X receptor improves viability of adipose-derived mesenchymal stem cells to attenuate myocardial ischemia injury through TLR4/NF-?B and Keap-1/Nrf-2 signaling pathways.

Publications

Activation of liver X receptor improves viability of adipose-derived mesenchymal stem cells to attenuate myocardial ischemia injury through TLR4/NF-κB and Keap-1/Nrf-2 signaling pathways.

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