Atorvastatin Improves Microenvironment to Enhance the Beneficial Effects of BMSCs Therapy in a Rabbit Model of Acute Myocardial Infarction

Qu, Zhe; Xu, Hongxin; Tian, Yihao; Jiang, Xuejun

doi:10.1159/000354445

Cited by 21 publications

(13 citation statements)

References 43 publications

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“…Most donor cells do not survive for prolonged periods in ischemic myocardium, which limits clinical application of cell-based therapies (25). Some recent studies show that inflammation and oxidative stress are major contributors to the acute death of engrafted stem cells (34,36).…”

Section: Discussionmentioning

confidence: 99%

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

C²,

Cheng³

et al. 2014

Antioxidants & Redox Signaling

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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.

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Section: Discussionmentioning

confidence: 99%

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

C²,

Cheng³

et al. 2014

Antioxidants & Redox Signaling

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“…The I/R model was established according to previously reported studies [20][21][22][23]. Briefly, animals were anesthetized i.p.…”

Section: In Vivo I/r Modelmentioning

confidence: 99%

“…After storage for 10 min at -20°C, the heart was cut into 5 or 6 transverse slices (1 mm thickness) across the long axis. Then, the slices were stained with 1% triphenyltetrazolium chloride (TTC, Amresco, USA) in citrate buffer solution (ph=7.4) for 10 min at 37°C, to delineate the area at risk (AAR) [20][21][22][23]. Afterwards, all slices were fixed with 4% paraformaldehyde, photographed and analyzed.…”

Section: Measurement Of Myocardial Infarction Sizementioning

confidence: 99%

Qiliqiangxin Protects Against Cardiac Ischemia-Reperfusion Injury via Activation of the mTOR Pathway

Zhou

Fang²,

Lin³

et al. 2015

Cell Physiol Biochem

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Background/Aims: Qiliqiangxin (QL) has been used for the treatment of chronic heart failure in China. Accumulating evidence suggests QL's cardio-protective effects on continuous myocardial ischemia. However, it is unclear whether QL has beneficial effects on cardiac ischemia-reperfusion (I/R) injury. Methods: A mouse model of cardiac I/R was established by ligation of the left anterior descending coronary artery for 45 minutes followed by reperfusion. The mice were treated with QL for three days before surgery and continually after I/R. Triphenyltetrazolium chloride staining, echocardiography and Masson's trichrome staining were used to determine infarct size, cardiac function, and fibrosis, respectively. Expression levels of phospho-mTOR (Ser2448), mTOR, phospho-4EBP (Ser65), 4EBP, phospho-Akt (Ser473) and Akt were detected by Western blotting. Results: At 1 day after I/R, QL treatment significantly reduced the infarct size of mice exposed to I/R. At 7 days after I/R, mortality was reduced in QL treated animals in comparison with the control group. In addition, QL treated mice showed increased left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) at 1 and 7 days after I/R. In agreement, Masson's trichrome staining demonstrated that interstitial fibrosis was less pronounced in QL treated mice compared with controls, suggesting that adverse left ventricular remodeling is attenuated in QL treated mice. Moreover, western blotting analysis demonstrated that QL activated the mTOR pathway, while mTOR inhibition via Rapamycin abolished the protective effects of QL against I/R injury. Conclusion: This study suggests that QL attenuates the progression of cardiac remodeling after I/R likely via mTOR activation. This represents a new application for QL in the prevention of I/R injury.

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“…MMP-2 is a key factor for micro-environmental adhesion, maturation and differentiation of stem cells [50,51], but also for the breakdown of extracellular matrix in normal physiological processes and tissue remodeling. Controversies exist with respect to the regulation of MMP-2 after MI.…”

Section: Discussionmentioning

confidence: 99%

Exploiting AT2R to Improve CD117 Stem Cell Function In Vitro and In Vivo - Perspectives for Cardiac Stem Cell Therapy

Ludwig¹,

Tölk²,

Skorska³

et al. 2015

Cell Physiol Biochem

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Background/Aims: CD117⁺ stem cell (SC) based therapy is considered an alternative therapeutic option for terminal heart disease. However, controversies exist on the effects of CD117⁺ SC implantation. In particular, the link between CD117⁺ SC function and angiotensin-II-type-2 receptor (AT2R) after MI is continuously discussed. We therefore asked whether 1) AT2R stimulation influences CD117⁺ SC properties in vitro and, 2) which effects can be ascribed to AT2R stimulation in vivo. Methods: We approached AT2R stimulation with Angiotensin II while simultaneously blocking its opponent receptor AT1 with Losartan. CD117 effects were dissected using a 2D-Matrigel assay and HL-1 co-culture in vitro. A model of myocardial infarction, in which we implanted EGFP+ CD117 SC, was further applied. Results: While we found indications for AT2R driven vasculogenesis in vitro, co-culture experiments revealed that CD117⁺ SC improve vitality of cardiomyocytes independently of AT2R function. Likewise, untreated CD117⁺ SC had a positive effect on cardiac function and acted cardioprotective in vivo. Conclusions: Therefore, our data show that transient AT2R stimulation does not significantly add to the beneficial actions of CD117⁺ SC in vivo. Yet, exploiting AT2R driven vasculogenis via an optimized AT2R stimulation protocol may become a promising tool for cardiac SC therapy.

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Atorvastatin Improves Microenvironment to Enhance the Beneficial Effects of BMSCs Therapy in a Rabbit Model of Acute Myocardial Infarction

Cited by 21 publications

References 43 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

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

Qiliqiangxin Protects Against Cardiac Ischemia-Reperfusion Injury via Activation of the mTOR Pathway

Exploiting AT2R to Improve CD117 Stem Cell Function In Vitro and In Vivo - Perspectives for Cardiac Stem Cell Therapy

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