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• Correction Volume 14, Issue 7 pp 3329-3330

  Correction for: Inhibition of CDK9 attenuates atherosclerosis by inhibiting inflammation and phenotypic switching of vascular smooth muscle cells

  Relevance score: 10.414442

  Shushi Huang, Wu Luo, Gaojun Wu, Qirui Shen, Zaishou Zhuang, Daona Yang, Jinfu Qian, Xiang Hu, Yan Cai, Nipon Chattipakorn, Weijian Huang, Guang Liang

  Keywords: atherosclerosis, CDK9, pharmacological inhibition, inflammation, phenotypic switching, vascular smooth muscle cells

  Published in Aging on April 14, 2022

• Research Paper Volume 13, Issue 11 pp 14892-14909

  Inhibition of CDK9 attenuates atherosclerosis by inhibiting inflammation and phenotypic switching of vascular smooth muscle cells

  Relevance score: 12.357479

  Shushi Huang, Wu Luo, Gaojun Wu, Qirui Shen, Zaishou Zhuang, Daona Yang, Jinfu Qian, Xiang Hu, Yan Cai, Nipon Chattipakorn, Weijian Huang, Guang Liang

  Keywords: atherosclerosis, CDK9, pharmacological inhibition, inflammation, phenotypic switching, vascular smooth muscle cells

  Published in Aging on June 8, 2021

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  Background: Recent studies have demonstrated a key role of vascular smooth muscle cell (VSMC) dysfunction in atherosclerosis. Cyclin-dependent kinases 9 (CDK9), a potential biomarker of atherosclerosis, was significantly increased in coronary artery disease patient serum and played an important role in inflammatory diseases. This study was to explore the pharmacological role of CDK9 inhibition in attenuating atherosclerosis.

  Methods: A small-molecule CDK9 inhibitor, LDC000067, was utilized to treat the high fat diet (HFD)-fed ApoE^-/- mice and human VSMCs.

  Results: The results showed that inflammation and phenotypic switching of VSMCs were observed in HFD-induced atherosclerosis in ApoE^-/- mice, which were accompanied with increased CDK9 in the serum and atherosclerotic lesions where it colocalized with VSMCs. LDC000067 treatment significantly suppressed HFD-induced inflammation, proliferation and phenotypic switching of VSMCs, resulting in reduced atherosclerosis in the ApoE^-/- mice, while had no effect on plasma lipids. Further in vitro studies confirmed that LDC000067 and siRNA-mediated CDK9 knockdown reversed ox-LDL-induced inflammation and phenotypic switching of VSMCs from a contractile phenotype to a synthetic phenotype via inhibiting NF-κB signaling pathway in human VSMCs.

  Conclusion: These results indicate that inhibition of CDK9 may be a novel therapeutic target for the prevention of atherosclerosis.

• Research Paper Volume 12, Issue 7 pp 6030-6036

  Elevated p38MAPK activity promotes neural stem cell aging

  Relevance score: 12.489779

  Leire Moreno-Cugnon, Olatz Arrizabalaga, Irantzu Llarena, Ander Matheu

  Keywords: p38MAPK, aging, neural stem cell, pharmacological inhibition

  Published in Aging on April 3, 2020

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  Age-progressive neural stem cell (NSC) dysfunction leads to impaired neurogenesis, cognitive decline and the onset of age-related neurodegenerative pathologies. p38MAPK signalling pathway limits stem cell activity during aging in several tissues. Its role in NSCs remains controversial. In this work, we show that p38MAPK activity increases in NSCs with age in the subventricular zone (SVZ) and its pharmacological inhibition is sufficient to rejuvenate their activity in vitro. These data reveal a cell-autonomous role for p38MAPK increase in decreasing NSC homeostasis with age. This information shed light in the role of p38MAPK in NSC aging.

  

  Increased p38MAPK activity in SVZ neurogenic niche with aging. (A) Representative immunofluorescence for P-p38MAPK in SVZ of young (2 month-old) and aged (over 24 month-old) C57BL/6J mice (n≥2). (B) Quantification of number of P-p38MAPK positive cells in this region. (C) MAPK11, MAPK12, MAPK13 and MAPK14 mRNA levels in SVZ of young (2 month-old) and aged (over 24 month-old) C57BL/6J mice (n≥4).

  
  
  

  

  p38MAPK activity regulates NSC/progenitor aging in vitro. (A) Quantification of neurospheres from young (2 month-old) and aged (over 24 month-old) C57BL/6J mice (n=3). (B) P-p38MAPK, SOX2 and p16^Ink4a expression in neurospheres derived from animals at the indicated ages (n=3). (C) Analysis of MAPK isoforms in neurospheres. (D) Representative image and (E) quantification of neurospheres derived from the SVZ of young and aged C57BL/6J mice treated with p38MAPK inhibitor (PH-797804) or control (DMSO) (n=4). (F) Quantification of the diameter of secondary neurospheres derived from aged mice treated with PH-797804 or control (n=4). (G) Representative western blot of P-p38MAPK, p38MAPK, SOX9 and ß-actin in 2^ry neurospheres from aged mice (n=2). (H) Quantification of Sox2 mRNA levels in aged cells (n=3).

  
  
  

  

  Pharmacological inhibition of p38MAPK rejuvenates NSC function in vitro. (A) Representative image and (B, C) quantification of number of neurospheres and their diameter at passage 2 (2^ry) and 7 (7^ry) from SVZ C57BL/6J mice (n=3). (D) Representative western blot of P-p38MAPK, SOX2, p16^Ink4a and ß-actin at indicated conditions (n=3). (E) Relative number of neurospheres formed from passage 7 cells treated with p38MAPK inhibitor (PH-797804) or control (DMSO) (n=3). (F) Quantification of the diameter of neurospheres from 7^ry passage treated with PH-797804 or control (n=3). (G) Sox2, Sox9 and Mkp1 expression in neurospheres maintained for passages (n=3).