Rosuvastatin Treatment Activates JAK-STAT Pathway and Increases Efficacy of Allogeneic Mesenchymal Stem Cell Transplantation in Infarcted Hearts

Xu, Hui; Yang, Yue-Jin; Qian, Hai-Yan; Tang, Yi-Da; Wang, Hong; Zhang, Qian

doi:10.1253/circj.cj-10-1275

Cited by 55 publications

(33 citation statements)

References 44 publications

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“…Similarly, its activation by a statin, rosuvastatin, exerts strong protective effects on MSCs. 34 Fryer et al first demonstrated that the DOR agonists, DPDPE and TAN-67, induced cardioprotection, and that treatment with the PKC antagonist, chelerythrine, completely abolished DADLE-and TAN-67-induced cardioprotection. 18 A variety of molecules released as a result of stress, including nitric oxide and oxygen radicals, activate PKC and other endogenous signal transduction cascades to produce protection.…”

Section: Signaling Pathway For Msc Survival By Dor Activationmentioning

confidence: 99%

“…Oxygen radicals, bradykinins, and adenosine are frequently reported to trigger activation of PKC for the opening of mitonchondrial KATP channel that mediates cell protection. 34 Stimulation of DOR appears to mimic ischemic preconditioning via opening of the mitochondrial KATP channel. 35 Gross et al reported that STAT3 activation is required for cardioprotection by opioids.…”

Section: Signaling Pathway For Msc Survival By Dor Activationmentioning

confidence: 99%

See 1 more Smart Citation

Delta-Opioid Receptor Activation Promotes Mesenchymal Stem Cell Survival via PKC/STAT3 Signaling Pathway

Higuchi

Masaaki

Zhu

et al. 2012

Circ J

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Section: Signaling Pathway For Msc Survival By Dor Activationmentioning

confidence: 99%

Section: Signaling Pathway For Msc Survival By Dor Activationmentioning

confidence: 99%

Delta-Opioid Receptor Activation Promotes Mesenchymal Stem Cell Survival via PKC/STAT3 Signaling Pathway

Higuchi

Masaaki

Zhu

et al. 2012

Circ J

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“…They can not only attenuate the inflammation and oxidative stress to provide a better microenvironment for implanted MSCs after AMI, but also increase the anti-apoptotic capacity of MSCs itself under H/SD condition, of which, both make statins a convincing candidate to deal with the ''low survival'' problem of MSCs mentioned previously [3,[13][14][15]. Several signaling pathways have been implicated in this protective role of statins, including AMP-activated protein kinase (AMPK), Janus kinase/ signal transducers and activators of the transcription, phosphatidylinositol 3-kinase (PI3K)/Akt, and mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ ERK1/2) pathways [13,14,16]. More recently, autophagy induction has been noticed as a novel way by which statins regulate cell survival and death [17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Autophagy Activation: A Novel Mechanism of Atorvastatin to Protect Mesenchymal Stem Cells from Hypoxia and Serum Deprivation via AMP-Activated Protein Kinase/Mammalian Target of Rapamycin Pathway

Zhang

Yang

Wang

et al. 2012

Stem Cells and Development

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155

114

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Autophagy is a complex ''self-eating'' process and could be utilized for cell survival under stresses. Statins, which could reduce apoptosis in mesenchymal stem cells (MSCs) during both ischemia and hypoxia/serum deprivation (H/SD), have been proved to induce autophagy in some cell lines. We have previously shown that atorvastatin (ATV) could regulate AMP-activated protein kinase (AMPK), a positive modulator of autophagy, in MSCs. Thus, we hypothesized that autophagy activation through AMPK and its downstream molecule mammalian target of rapamycin (mTOR) may be a novel mechanism of ATV to protect MSCs from apoptosis during H/SD. Here, we demonstrated that H/SD induced autophagy in MSCs significantly as identified by increasing acidic vesicular organelle-positive cells, type II of light chain 3 (LC3-II) expression, and autophagosome formation. The levels of H/SD-induced apoptosis were increased by autophagy inhibitor 3-methyladenine (3-MA) while decreased by rapamycin, an autophagic inducer. ATV further enhanced the autophagic activity observed in MSCs exposed to H/SD. Treatment with 3-MA attenuated ATV-induced autophagy and abrogated the protective effects of ATV on MSC apoptosis, while rapamycin failed to cause additional effects on either autophagy or apoptosis compared with ATV alone. The phosphorylation of AMPK was upregulated whereas the phosphorylation of mTOR was downregulated in ATV-treated MSCs, which were both attenuated by AMPK inhibitor compound C. Further, treatment with compound C reduced the ATV-induced autophagy in MSCs under H/SD. These data suggest that autophagy plays a protective role in H/SD-induced apoptosis of MSCs, and ATV could effectively activate autophagy via AMPK/mTOR pathway to enhance MSC survival during H/SD.

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“…The mitochondrial STAT3 (signal transducer and activator of transcription 3) system represents another central element of cardioprotection [29]. Rosuvastatin was proven to improve the efficacy of stem cell transplantation in infarcted hearts by activation of the STAT3 signaling pathway [30]. However, considering acute statin effects in the setting of statin-recapture therapy, there is lacking evidence for the involvement of STAT3 signaling in the reactivation of pleiotropic statin effects.…”

Section: Discussionmentioning

confidence: 99%

Rosuvastatin Reloading before Cardiac Surgery with Cardiopulmonary Bypass

Kuhn¹,

Liakopoulos²,

Deppe³

et al. 2013

Eur Surg Res

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Background/Purpose: Recent evidence suggests that statin-mediated cardioprotection after chronic statin therapy decreases over time and can be reactivated by preprocedural high-dose statin reloading therapy. We tested in a porcine cardiopulmonary bypass (CPB) model whether statin-related cardioprotection is further enhanced by a preoperative rosuvastatin reloading therapy. Methods: Control (n = 6), rosuvastatin-pretreated (n = 6; 20 mg/day for 7 days p.o.) and rosuvastatin-reloaded (n = 6; p.o. treatment plus 0.10 mg/kg/h i.v. during surgery) pigs (Deutsche Landrasse) were subjected to CPB for 2 h with 1 h of cardioplegic cardiac arrest. Systemic hemodynamics, cardiac index (CI), coronary blood flow (CBF) and left ventricular (LV) function [pressure-volume area (PVA), preload recruitable stroke work (PRSW)] were determined before and 4 h after CPB. Myocardial expression (PCR) and protein content (Western blot) of endothelial NO synthase (eNOS) and phosphatase and tensin homolog deleted on chromosome ten (PTEN) were measured, and right coronary relaxation was assessed postmortem. All data are given as mean ± SD. Results: Preoperative plasma LDL, HDL and cholesterol did not differ between treatment groups. Compared to control, oral treatment improved post-CPB CI, CBF, first derivative of maximal LV-pressure (LVdp/dt) and PVA (p < 0.05). Significant enhancement was achieved with perioperative reloading therapy (CI: 5.2 ± 1.0 vs. 3.9 ± 1.5 l/min/m²; CBF: 76 ± 32 vs. 43 ± 8 ml/min; LVdp/dt: 1,980 ± 333 vs. 1,249 ± 461 mm Hg/s; PVA: 6,954 ± 941 vs. 3,252 ± 1,822 mm Hg·ml; p < 0.05) with improved in vitro NO-dependent coronary relaxation (102 ± 10 vs. 79 ± 14%; p = 0.003). Irrespective of recapture therapy statin pretreatment augmented myocardial eNOS and PTEN (p < 0.05), but failed to increase cardiac eNOS or PTEN expression after CPB. Conclusions: Periprocedural statin reloading therapy enhances myocardial and coronary function after cardiac surgery with CPB and may therefore provide a valuable therapeutic approach for the reduction of myocardial ischemia-reperfusion injury.

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Rosuvastatin Treatment Activates JAK-STAT Pathway and Increases Efficacy of Allogeneic Mesenchymal Stem Cell Transplantation in Infarcted Hearts

Cited by 55 publications

References 44 publications

Delta-Opioid Receptor Activation Promotes Mesenchymal Stem Cell Survival via PKC/STAT3 Signaling Pathway

Delta-Opioid Receptor Activation Promotes Mesenchymal Stem Cell Survival via PKC/STAT3 Signaling Pathway

Autophagy Activation: A Novel Mechanism of Atorvastatin to Protect Mesenchymal Stem Cells from Hypoxia and Serum Deprivation via AMP-Activated Protein Kinase/Mammalian Target of Rapamycin Pathway

Rosuvastatin Reloading before Cardiac Surgery with Cardiopulmonary Bypass

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