TY - JOUR
T1 - MRTFA overexpression promotes conversion of human coronary artery smooth muscle cells into lipid-laden foam cells
AU - Alajbegovic, Azra
AU - Holmberg, Johan
AU - Daoud, Fatima
AU - Rippe, Catarina
AU - Kalliokoski, Gabriella
AU - Ekman, Mari
AU - Daudi, Sébastien
AU - Ragnarsson, Sigurdur
AU - Swärd, Karl
AU - Albinsson, Sebastian
PY - 2021/6/1
Y1 - 2021/6/1
N2 - Objective: Smooth 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 results: Using 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. Conclusions: This 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.
AB - Objective: Smooth 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 results: Using 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. Conclusions: This 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.
KW - Atherosclerosis
KW - LDL receptor
KW - Myocardin
KW - Pinocytosis
KW - Transdifferentiation
U2 - 10.1016/j.vph.2021.106837
DO - 10.1016/j.vph.2021.106837
M3 - Article
C2 - 33516965
AN - SCOPUS:85100647586
VL - 138
JO - Vascular Pharmacology
JF - Vascular Pharmacology
SN - 1537-1891
M1 - 106837
ER -