Persistent Hypoxia with Intermittent Aggravation Causes Imbalance in Smad3/Myocardin-Related Transcription Factor Signaling with Consequent Endothelial Senescence and Pulmonary Arterial Remodeling.

Article

Author: Xie, Jiang ; Zhang, Jing ; Zhang, Hehe ; Singh, Prachi ; Li, Jingrui ; Hu, Jiaxin ; Li, Fei

Loss of Smad3 and the consequent activation of myocardin-related transcription factor (MRTF) are associated with vascular pathologies. This study aimed to examine the impact of persistent hypoxia with intermittent aggravation (PI hypoxia) on cellular senescence and pulmonary arterial remodeling mediated by the Smad3/MRTF imbalance. We examined the effects of PI hypoxia on the Smad3/MRTF pathway and cellular senescence using human pulmonary artery endothelial cells (HPAECs) and in vivo studies in rats. The senescent degree was evaluated using β-galactosidase staining, p16 quantitation and the measurement of senescence-associated secretory phenotype. Structural data in the pathological analysis of pulmonary artery remodeling were collected. Compared to the control, HPAECs and pulmonary tissue from rats exposed to PI hypoxia showed a significantly higher senescent degree, lower expression of Smad3, and higher MRTF levels. The overexpression of Smad3 significantly mitigated HPAECs senescence in vitro. Further, treatment with CCG-203971, which inhibits MRTF, increased Smad3 levels and reduced β-galactosidase positive cells in rat lung tissue. This intervention also alleviated PI hypoxia-induced pathological changes, including remodeling indices of pulmonary arterial thickening, muscularization, and collagen formation. In conclusion, imbalanced Smad3/MRTF signaling is linked to PI hypoxia-induced senescence and pulmonary arterial remodeling, making it a potential therapeutic target for patients with sleep apnea and chronic obstructive pulmonary disease.

01 Jun 2021·Vascular PharmacologyQ3 · MEDICINE

MRTFA overexpression promotes conversion of human coronary artery smooth muscle cells into lipid-laden foam cells

Q3 · MEDICINE

Article

Author: Rippe, Catarina ; Kalliokoski, Gabriella ; Swärd, Karl ; Daoud, Fatima ; Albinsson, Sebastian ; Ekman, Mari ; Alajbegovic, Azra ; Ragnarsson, Sigurdur ; Daudi, Sébastien ; Holmberg, Johan

OBJECTIVESmooth muscle cells contribute significantly to lipid-laden foam cells in atherosclerotic plaques. However, the underlying mechanisms transforming smooth muscle cells into foam cells are poorly understood. The purpose of this study was to gain insight into the molecular mechanisms regulating smooth muscle foam cell formation.APPROACH AND RESULTSUsing human coronary artery smooth muscle cells we found that the transcriptional co-activator MRTFA promotes lipid accumulation via several mechanisms, including direct transcriptional control of LDL receptor, enhanced fluid-phase pinocytosis and reduced lipid efflux. Inhibition of MRTF activity with CCG1423 and CCG203971 significantly reduced lipid accumulation. Furthermore, we demonstrate enhanced MRTFA expression in vascular remodeling of human vessels.CONCLUSIONSThis study demonstrates a novel role for MRTFA as an important regulator of lipid homeostasis in vascular smooth muscle cells. Thus, MRTFA could potentially be a new therapeutic target for inhibition of vascular lipid accumulation.

01 Dec 2020·Inflammation and RegenerationQ3 · MEDICINE

Migration arrest of chemoresistant leukemia cells mediated by MRTF-SRF pathway

Q3 · MEDICINE

ArticleOA

Author: Motooka, Daisuke ; Ishii, Masaru ; Sudo, Takao ; Morimatsu, Maho ; Seno, Shigeto ; Okuzaki, Daisuke ; Yamashita, Erika ; Kikuta, Junichi ; Mizuno, Hiroki

BACKGROUNDDormant chemotherapy-resistant leukemia cells can survive for an extended period before relapse. Nevertheless, the mechanisms underlying the development of chemoresistance in vivo remain unclear.METHODSUsing intravital bone imaging, we characterized the behavior of murine acute myeloid leukemia (AML) cells (C1498) in the bone marrow before and after chemotherapy with cytarabine.RESULTSProliferative C1498 cells exhibited high motility in the bone marrow. Cytarabine treatment impaired the motility of residual C1498 cells. However, C1498 cells regained their migration potential after relapse. RNA sequencing revealed that cytarabine treatment promoted MRTF-SRF pathway activation. MRTF inhibition using CCG-203971 augmented the anti-tumor effects of chemotherapy in our AML mouse model, as well as suppressed the migration of chemoresistant C1498 cells.CONCLUSIONSThese results provide novel insight into the role of cell migration arrest on the development of chemoresistance in AML, as well as provide a strong rationale for the modulation of cellular motility as a therapeutic target for refractory AML.

100 Deals associated with CCG-203971

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Indication	Highest Phase	Country/Location	Organization	Date
Glaucoma, Open-Angle	Preclinical	CA	McMaster University	01 Jul 2019
Glaucoma, Open-Angle	Preclinical	DE	The Fraunhofer Institute for Cell Therapy & Immunology	01 Jul 2019
Diabetes Mellitus, Type 2	Preclinical	US	Genesis Biosciences LLC	-

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