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ABSTRACT: Stem cell-based therapy is a promising option for the treatment of ischemic heart diseases. As to a successful stem cell-based therapy, one of the most important issues is that the stable engraftment and survival of implanted stem cells in cardiac microenvironment. There are evidences suggest that pharmacological treatment devoted to regulate stem cell function might represent a potential new therapeutic strategy and are drawing nearer to becoming a part of treatment in clinical settings. Statins could exert cholesterol-independent or pleiotropic effects to cardiovascular system. Recent studies have shown that statins could modulate the biological characteristics and function of various stem cells, thus could be an effective method to facilitate stem cell therapy. This review will focus on statins and their modulation effects on various stem cells.
Ageing research reviews 04/2012; 12(1):1-7. · 5.62 Impact Factor
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ABSTRACT: 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.
Stem cells and development 02/2012; 21(8):1321-32. · 4.15 Impact Factor
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ABSTRACT: The effect of mesenchymal stem cells (MSCs) transplantation is poor because of the harsh environment post infarction. Our previous studies have proven that Statins could enhance the implanted bone marrow MSCs survival, but the exact mechanism remained to be clarified. We hypothesized that atorvastatin (Ator) could protect MSCs from hypoxia and serum-free (H/SF) induced apoptosis and investigated the potential mechanisms.
Chinese mini-swine's bone marrow derived MSCs were cultured in vitro and exposed to hypoxia and H/SF, Ator of various concentrations (0.001 - 10 µmol/L), AMPK inhibitor-compound C (CC), PI3K inhibitor-LY294002 (LY), Ator + CC and Ator + LY. Cell apoptosis was assessed using Annexin V/Propidine Iodine kit by flow cytometry. Phosphorylation of AMPK, Akt, endothelial nitric oxide synthase (eNOS) level and phosphorylation were tested with Western blot. Real Time-PCR was performed to analyze the gene expression of AMPK, Akt and eNOS.
MSCs apoptosis in Ator (0.01 - 10 µmol/L) treated H/SF groups was significantly reduced compared with H/SF group (1.94% - 6.10% vs. 10.94%, P < 0.01 or 0.05). Apoptosis was higher in Ator + CC group than in 1 µmol/L Ator group (4.94% ± 0.98% vs. 2.59% ± 0.84%, P < 0.01) and similar between Ator + LY and 1 µmol/L Ator group (2.02% ± 0.45% vs. 2.59% ± 0.84%, P > 0.05). The gene expressions of AMPK, Akt and eNOS were significantly upregulated in atorvastatin treated groups. Meanwhile, phosphorylation of AMPK and eNOS increased in MSCs treated with atorvastatin (P < 0.01 or 0.05). Phosphorylation of eNOS significantly correlated with AMPK phosphorylation (r = 0.599, P = 0.004), but not with Akt phosphorylation (P = 0.263).
Atorvastatin can protect MSCs from H/SF induced apoptosis through AMPK pathway, which resulting in activation of eNOS.
Zhonghua xin xue guan bing za zhi [Chinese journal of cardiovascular diseases] 11/2011; 39(11):1033-8.
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ABSTRACT: Resveratrol is a well-known antioxidant that exists in grape skin/seed, red wine, and the root of Polygonum cuspidatum, a traditional Chinese and Japanese medicinal material. Studies have found that resveratrol has many interesting properties, including anti-carcinogenic properties, anti-microbial and antiviral effects, the ability to reverse dyslipidemia and obesity, the ability to attenuate hyperglycemia and hyperinsulinemia, and the ability to protect endothelial function. Heart failure is the final consequence of the majority of cardiovascular diseases, and resveratrol has been shown to directly attenuate heart contraction. The cardiovascular protective capacities of resveratrol are associated with multiple molecular targets and may lead to the development of novel therapeutic strategies for atherosclerosis, ischemia/reperfusion, metabolic syndrome, and heart failure. This article will mainly review recently published basic researches about the protective cardiovascular effects of resveratrol because these results may lead to the development of new clinical therapeutics in patients.
Heart Failure Reviews 06/2011; 17(3):437-48. · 3.20 Impact Factor
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ABSTRACT: Widespread death of implanted cells hampers the development of stem cell therapy for acute myocardial infarction (AMI). Our previous studies indicated that statins can protect implanted mesenchymal stem cells (MSCs) against the post-infarct microenvironment, thus increasing the therapeutic effect. However, the underlying mechanisms are unclear. The JAK-STAT pathway participates in regulation of stress responses of the myocardium to various insults. This study aimed to detect whether rosuvastatin (ROSU) facilitates the survival, engraftment, and differentiation of allogeneic bone marrow-derived MSCs in the post-infarct heart via the JAK-STAT signaling pathway.
Female Sprague-Dawley rats were randomized into 5 groups: AMI (control), ROSU gavage (group R), MSCs transplantation (group M), MSCs and ROSU (group M+R), or MSCs, ROSU and a JAK2 inhibitor AG-490 (group M+R+AG). MSCs from male rats were injected into the myocardium 1 week after AMI. Cardiac function and histology, as well as the expression of Y-chromosomal genes and JAK-STAT signaling proteins, were examined at 4 weeks after transplantation. Better functional recovery, increased survival and differentiation of MSCs occurred in group M+R. Furthermore, phosphorylation of JAK2 and STAT3 was higher in group M+R. The effects of ROSU, as well as of activated JAK-STAT proteins, could be attenuated by AG-490.
ROSU treatment improves the efficacy of stem cell transplantation in infarcted hearts by activation of the JAK2-STAT3 signaling pathway.
Circulation Journal 05/2011; 75(6):1476-85. · 3.77 Impact Factor
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ABSTRACT: In recent years, stem cell-based therapy has been given increased attention in terms of its potential contribution to cardiac regeneration and repair, after acute myocardial infarction (AMI). The published studies have identified many kinds of stem cells with the ability to regenerate and repair damaged myocardium after AMI. These include embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), multipotent adult progenitor cells, unrestricted somatic stem cells, etc. More recently, very small embryonic-like stem cells (VSELs) were identified from murine, as a population of very small CXCR4(+) Lin(-) CD45(-) cells and from human, as a population of very small CD34(+) CD133(+) CXCR4(+) Lin(-) CD45(-) cells. These cells exhibit beneficial effects on improving cardiac function and attenuating cardiac remodeling after AMI. However, the mechanisms underlying the benefits associated with VSELs therapy, in cardiac regeneration and repair, remain poorly understood. This review summarizes the current studies on cardiac repair with VSELs after AMI, and discusses the potential mechanisms and implications of these cells in cardiac repair.
Ageing research reviews 10/2010; 10(1):173-7. · 5.62 Impact Factor
