Myocardin-related transcription factor-A-overexpressing bone marrow stem cells protect cardiomyocytes and alleviate cardiac damage in a rat model of acute myocardial infarction

Zhong, Ze; Hu, Jiaqing; Wu, Xindong; Sun, Yong; Jiang, Jun

doi:10.3892/ijmm.2015.2261

Cited by 7 publications

(4 citation statements)

References 31 publications

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“…This functional improvement is attributed to the ability of TG-0054 to mobilize the CD271-MSCs and reduce both plasma and myocardial cytokine levels [ 84 ]. BM-MSCs overexpressing myocardin-related transcription factor-A ( MRTF-A ) prevent primary cardiomyocyte apoptosis caused by H 2 O 2 , and thus help in reversing the cardiac damage after MI [ 85 ]. Similarly, overexpression of CREG in intramyocardially implanted BM-MSCs resulted in increased angiogenesis and reduced apoptosis and fibrosis [ 12 ].…”

Section: Main Textmentioning

confidence: 99%

Mesenchymal stem cells in cardiac regeneration: a detailed progress report of the last 6 years (2010–2015)

2016

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Mesenchymal stem cells have been used for cardiovascular regenerative therapy for decades. These cells have been established as one of the potential therapeutic agents, following several tests in animal models and clinical trials. In the process, various sources of mesenchymal stem cells have been identified which help in cardiac regeneration by either revitalizing the cardiac stem cells or revascularizing the arteries and veins of the heart. Although mesenchymal cell therapy has achieved considerable admiration, some challenges still remain that need to be overcome in order to establish it as a successful technique. This in-depth review is an attempt to summarize the major sources of mesenchymal stem cells involved in myocardial regeneration, the significant mechanisms involved in the process with a focus on studies (human and animal) conducted in the last 6 years and the challenges that remain to be addressed.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-016-0341-0) contains supplementary material, which is available to authorized users.

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Section: Main Textmentioning

confidence: 99%

Mesenchymal stem cells in cardiac regeneration: a detailed progress report of the last 6 years (2010–2015)

2016

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“…The activation of MRTF-A in mesenchymal stem cells (MSC) had been shown to play a role in MSC-mediated angiogenesis and induce MSC differentiation into several cell types, including endothelial and contractile smooth muscle cells [43–45]. Studies using MRTF-A knockdown implicate it in myotube formation and SRF-dependent activation of muscle genes in vitro [41] and overexpression of MRTF-A in bone marrow stem cells has been shown to be protective following myocardial infarction in rats (MI) [46]. …”

Section: Introductionmentioning

confidence: 99%

Sphingosine 1-phosphate elicits RhoA-dependent proliferation and MRTF-A mediated gene induction in CPCs

Castaldi

Chesini

Taylor

et al. 2016

Cellular Signalling

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Although c-kit+ cardiac progenitor cells (CPCs) are currently used in clinical trials there remain considerable gaps in our understanding of the molecular mechanisms underlying their proliferation and differentiation. G-protein coupled receptors (GPCRs) play an important role in regulating these processes in mammalian cell types thus we assessed GPCR mRNA expression in c-kit+ cells isolated from adult mouse hearts. Our data provide the first comprehensive overview of the distribution of this fundamental class of cardiac receptors in CPCs and reveals notable distinctions from that of adult cardiomyocytes. We focused on GPCRs that couple to RhoA activation in particular those for sphingosine-1 -phosphate (S1P). The S1P2 and S1P3 receptors are the most abundant S1P receptor subtypes in mouse and human CPCs while cardiomyocytes express predominantly S1P1 receptors. Treatment of CPCs with S1P, as with thrombin and serum, increased proliferation through a pathway requiring RhoA signaling, as evidenced by significant attenuation when Rho was inhibited by treatment with C3 toxin. Further analysis demonstrated that both S1P- and serum- induced proliferation are regulated through the S1P2 and S1P3 receptor subtypes which couple to Gα12/13 to elicit RhoA activation. The transcriptional co-activator MRTF-A was activated by S1P as assessed by its nuclear accumulation and induction of a RhoA/MRTF-A luciferase reporter. In addition S1P treatment increased expression of cardiac lineage markers Mef2C and GATA4 and the smooth muscle marker GATA6 through activation of MRTF-A. In conclusion, we delineate an S1P–regulated signaling pathway in CPCs that introduces the possibility of targeting S1P2/3 receptors, Gα12/13 or RhoA to influence the proliferation and commitment of c-kit+ CPCs and improve the response of the myocardium following injury.

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“…However, even for the high risk population of AD, care should be taken for prophylactic chronic MRTF-A inhibition, because the function and its (patho)physiological role of MRTF-A seem context-dependent. Indeed, MRTF-A may play a protective role in neuronal and myocardial ischemia [30,39,40,48,49]. Another potential opportunity is the acute inhibition of MRTF-A after AD development to prevent further tissue destruction.…”

Section: Plos Onementioning

confidence: 99%

MRTF-A promotes angiotensin II-induced inflammatory response and aortic dissection in mice

et al. 2020

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Aortic dissection (AD) is a major cause of acute aortic syndrome with high mortality due to the destruction of aortic walls. Although recent studies indicate the critical role of inflammation in the disease mechanism of AD, it is unclear how inflammatory response is initiated. Here, we demonstrate that myocardin-related transcription factor A (MRTF-A), a signal transducer of humoral and mechanical stress, plays an important role in pathogenesis of AD in a mouse model. A mouse model of AD was created by continuous infusion of angiotensin II (AngII) that induced MRTF-A expression and caused AD in 4 days. Systemic deletion of Mrtfa gene resulted in a marked suppression of AD development. Transcriptome and gene annotation enrichment analyses revealed that AngII infusion for 1 day caused pro-inflammatory and pro-apoptotic responses before AD development, which were suppressed by Mrtfa deletion. AngII infusion for 1 day induced pro-inflammatory response, as demonstrated by expressions of Il6, Tnf, and Ccl2, and apoptosis of aortic wall cells, as detected by TUNEL staining, in an MRTF-A-dependent manner. Pharmacological inhibition of MRTF-A by CCG-203971 during AngII infusion partially suppressed AD phenotype, indicating that acute suppression of MRTF-A is effective in preventing the aortic wall destruction. These results indicate that MRTF-A transduces the stress of AngII challenge to the pro-inflammatory and proapoptotic responses, ultimately leading to AD development. Intervening this pathway may represent a potential therapeutic strategy.

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Myocardin-related transcription factor-A-overexpressing bone marrow stem cells protect cardiomyocytes and alleviate cardiac damage in a rat model of acute myocardial infarction

Cited by 7 publications

References 31 publications

Mesenchymal stem cells in cardiac regeneration: a detailed progress report of the last 6 years (2010–2015)

Mesenchymal stem cells in cardiac regeneration: a detailed progress report of the last 6 years (2010–2015)

Sphingosine 1-phosphate elicits RhoA-dependent proliferation and MRTF-A mediated gene induction in CPCs

MRTF-A promotes angiotensin II-induced inflammatory response and aortic dissection in mice

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