scholarly journals MiR-223-3p in Cardiovascular Diseases: A Biomarker and Potential Therapeutic Target

2021 ◽  
Vol 7 ◽  
Author(s):  
Meng-Wan Zhang ◽  
Yun-Jie Shen ◽  
Jing Shi ◽  
Jian-Guang Yu
Keyword(s):  
Cardiovascular Diseases ◽  
Protein Kinase ◽  
Signaling Pathways ◽  
Therapeutic Target ◽  
Target Genes ◽  
Cell Function ◽  
Hypoxia Inducible Factor ◽  
Mitogen Activated Protein Kinase ◽  
Circulatory Disturbance ◽  
Pyrin Domain

Cardiovascular diseases, involving vasculopathy, cardiac dysfunction, or circulatory disturbance, have become the major cause of death globally and brought heavy social burdens. The complexity and diversity of the pathogenic factors add difficulties to diagnosis and treatment, as well as lead to poor prognosis of these diseases. MicroRNAs are short non-coding RNAs to modulate gene expression through directly binding to the 3′-untranslated regions of mRNAs of target genes and thereby to downregulate the protein levels post-transcriptionally. The multiple regulatory effects of microRNAs have been investigated extensively in cardiovascular diseases. MiR-223-3p, expressed in multiple cells such as macrophages, platelets, hepatocytes, and cardiomyocytes to modulate their cellular activities through targeting a variety of genes, is involved in the pathological progression of many cardiovascular diseases. It participates in regulation of several crucial signaling pathways such as phosphatidylinositol 3-kinase/protein kinase B, insulin-like growth factor 1, nuclear factor kappa B, mitogen-activated protein kinase, NOD-like receptor family pyrin domain containing 3 inflammasome, and ribosomal protein S6 kinase B1/hypoxia inducible factor 1 α pathways to affect cell proliferation, migration, apoptosis, hypertrophy, and polarization, as well as electrophysiology, resulting in dysfunction of cardiovascular system. Here, in this review, we will discuss the role of miR-223-3p in cardiovascular diseases, involving its verified targets, influenced signaling pathways, and regulation of cell function. In addition, the potential of miR-223-3p as therapeutic target and biomarker for diagnosis and prediction of cardiovascular diseases will be further discussed, providing clues for clinicians.

scholarly journals Multilevel regulation of HIF-1 signaling by TTP

2012 ◽  
Vol 23 (20) ◽  
pp. 4129-4141 ◽  
Author(s):  
Michael Fähling ◽  
Anja Bondke Persson ◽  
Bertram Klinger ◽  
Edgar Benko ◽  
Andreas Steege ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Posttranscriptional Regulation ◽  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Adaptation To Hypoxia ◽  
Mrna Stabilization ◽  
Physiological Importance ◽  
Multilevel Regulation

Hypoxia-inducible factor-1 (HIF-1) is a well-studied transcription factor mediating cellular adaptation to hypoxia. It also plays a crucial role under normoxic conditions, such as in inflammation, where its regulation is less well understood. The 3′-untranslated region (UTR) of HIF-1α mRNA is among the most conserved UTRs in the genome, hinting toward posttranscriptional regulation. To identify potential trans factors, we analyzed a large compilation of expression data. In contrast to its known function of being a negative regulator, we found that tristetraprolin (TTP) positively correlates with HIF-1 target genes. Mathematical modeling predicts that an additional level of posttranslational regulation of TTP can explain the observed positive correlation between TTP and HIF-1 signaling. Mechanistic studies revealed that TTP indeed changes its mode of regulation from destabilizing to stabilizing HIF-1α mRNA upon phosphorylation by p38 mitogen-activated protein kinase (MAPK)/MAPK-activated protein kinase 2. Using a model of monocyte-to-macrophage differentiation, we show that TTP-driven HIF-1α mRNA stabilization is crucial for cell migration. This demonstrates the physiological importance of a hitherto-unknown mechanism for multilevel regulation of HIF-1α in normoxia.

Protein Kinase C – Possible Therapeutic Target to Treat Cardiovascular Diseases

2010 ◽  
Vol 10 (4) ◽  
pp. 292-308 ◽  
Author(s):  
Yamini S. Bynagari-Settipalli ◽  
Ramya Chari ◽  
Laurie Kilpatrick ◽  
Satya P. Kunapuli
Keyword(s):  
Protein Kinase C ◽  
Cardiovascular Diseases ◽  
Protein Kinase ◽  
Therapeutic Target ◽  
Kinase C

scholarly journals TRAF6-Dependent Mitogen-Activated Protein Kinase Activation Differentially Regulates the Production of Interleukin-12 by Macrophages in Response to Toxoplasma gondii

2004 ◽  
Vol 72 (10) ◽  
pp. 5662-5667 ◽  
Author(s):  
Nicola J. Mason ◽  
Jim Fiore ◽  
Takashi Kobayashi ◽  
Katherine S. Masek ◽  
Yongwon Choi ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Toxoplasma Gondii ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Interleukin 12 ◽  
Wild Type ◽  
Kinase Activation ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

ABSTRACT The production of interleukin-12 (IL-12) is critical to the development of innate and adaptive immune responses required for the control of intracellular pathogens. Many microbial products signal through Toll-like receptors (TLR) and activate NF-κB family members that are required for the production of IL-12. Recent studies suggest that components of the TLR pathway are required for the production of IL-12 in response to the parasite Toxoplasma gondii; however, the production of IL-12 in response to this parasite is independent of NF-κB activation. The adaptor molecule TRAF6 is involved in TLR signaling pathways and associates with serine/threonine kinases involved in the activation of both NF-κB and mitogen-activated protein kinase (MAPK). To elucidate the intracellular signaling pathways involved in the production of IL-12 in response to soluble toxoplasma antigen (STAg), wild-type and TRAF6−/− mice were inoculated with STAg, and the production of IL-12(p40) was determined. TRAF6−/− mice failed to produce IL-12(p40) in response to STAg, and TRAF6−/− macrophages stimulated with STAg also failed to produce IL-12(p40). Studies using Western blot analysis of wild-type and TRAF6−/− macrophages revealed that stimulation with STAg resulted in the rapid TRAF6-dependent phosphorylation of p38 and extracellular signal-related kinase, which differentially regulated the production of IL-12(p40). The studies presented here demonstrate for the first time that the production of IL-12(p40) in response to toxoplasma is dependent upon TRAF6 and p38 MAPK.

scholarly journals Epstein-Barr Virus (EBV) Tegument Protein BGLF2 Promotes EBV Reactivation through Activation of the p38 Mitogen-Activated Protein Kinase

2015 ◽  
Vol 90 (2) ◽  
pp. 1129-1138 ◽  
Author(s):  
XueQiao Liu ◽  
Jeffrey I. Cohen
Keyword(s):  
Protein Kinase ◽  
Signaling Pathways ◽  
Epstein Barr Virus ◽  
Virus Production ◽  
Mitogen Activated Protein Kinase ◽  
Tegument Protein ◽  
Barr Virus ◽  
Ebv Reactivation ◽  
Mitogen Activated Protein ◽  
Epstein Barr

ABSTRACTEpstein-Barr virus (EBV) is a ubiquitous gammaherpesvirus associated with both B cell and epithelial cell malignancies. EBV infection of B cells triggers activation of several signaling pathways that are critical for cell survival, virus latency, and growth transformation. To identify EBV proteins important for regulating cell signaling, we used a proteomic approach to screen viral proteins for AP-1 and NF-κB promoter activity in AP-1– and NF-κB–luciferase reporter assays. We found that EBV BGLF2 activated AP-1 but not NF-κB reporter activity. Expression of EBV BGLF2 in cells activated p38 and c-Jun N-terminal kinase (JNK), both of which are important for mitogen-activated protein kinase (MAPK) signaling. Deletion of the carboxyl-terminal 66 amino acids of BGLF2 reduced the ability of BGLF2 to activate JNK and p38. Expression of BGLF2 enhanced BZLF1 expression in latently EBV-infected lymphoblastoid cell lines, and knockdown of BGLF2 reduced EBV reactivation induced by IgG cross-linking. Expression of BGLF2 induced BZLF1 expression and virus production in EBV-infected gastric carcinoma cells. BGLF2 enhanced BZLF1 expression and EBV production by activating p38; chemical inhibition of p38 and MAPK/ERK kinases 1 and 2 (MEK1/2) reduced expression of BZLF1 and virus production induced by BGLF2. In summary, the EBV tegument protein BGLF2, which is delivered to the cell at the onset of virus infection, activates the AP-1 pathway and enhances EBV reactivation and virus production.IMPORTANCEEpstein-Barr virus (EBV) is associated with both B cell and epithelial cell malignancies, and the virus activates multiple signaling pathways important for its persistence in latently infected cells. We identified a viral tegument protein, BGLF2, which activates members of the mitogen-activated protein kinase signaling pathway. Expression of BGLF2 increased expression of EBV BZLF1, which activates a switch from latent to lytic virus infection, and increased production of EBV. Inhibition of BGFL2 expression or inhibition of p38/MAPK, which is activated by BGLF2, reduced virus reactivation from latency. These results indicate that a viral tegument protein which is delivered to cells upon infection activates signaling pathways to enhance virus production and facilitate virus reactivation from latency.

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