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

Abstract

Aims: 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. Results: 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-a 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 IjBa phosphorylation and NF-jB-p65 nuclear translocation, which resulted in accelerated Keap-1 protein degradation, enhanced Nrf-2 nuclear translocation, and increased HO-1 protein expression. Innovation and Conclusion: LXR agonist can enhance the functional survival of transplanted AD-MSCs in infarcted myocardium, at least partially, via modulation of the TLR4/NF-jB 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. Antioxid. Redox Signal. 21, 2543-2557.

Enhanced Cardioprotection by Human Endometrium Mesenchymal Stem Cells Driven by Exosomal MicroRNA-21

“…Our results suggest that MSCs derived from the endometrium have greater therapeutic potential compared with cells derived from bone marrow or adipose tissue, the two most common sources of therapeutic MSCs , . We report stronger paracrine effects of EnMSC on cellular apoptosis and angiogenesis parameters in vitro and in vivo and greater myocardial salvage and enhanced cardiac function after MI in the EnMSC‐treatment groups.…”

Pirfenidone controls the feedback loop of the AT1R/p38 MAPK/renin-angiotensin system axis by regulating liver X receptor-α in myocardial infarction-induced cardiac fibrosis

“…Kuipers et al . found that T09, an LXR-α agonist, decreases AT1R and p38 MAPK in wild-type mice but not in LXR-α −/− mice1132. Therefore, the authors speculated that LXR-α plays a vital role in the positive feedback loop between the AT1R/p38 MAPK pathway and RAS.…”

Interferon Regulatory Factor Signalings in Cardiometabolic Diseases

“…263 Most recently, researchers reported that TLR3, the major TLR member that is responsible for the activation of IRF3 and IRF7, acted as a promoter of I/R-induced cardiac injury. 261, 264 Wang et al 265 also reported that the inactivation of TLR4/NF-κB and Keap-1/NRF-2 (nuclear factor, erythroid derived 2) signalings involved in liver X receptor-regulated cardiac repair and functional improvement post MI injury. According to immune signaling, the activation of TLRs may recruit adaptor proteins and may subsequently activate downstream factors to regulate the expression and function of IRFs, resulting in the induction of inflammatory and apoptotic responses.…”