Abstract
Background-Efferocytosis is a process by which dead and dying cells are removed by phagocytic cells. Efferocytosis by macrophages is thought to curb the progression of atherosclerosis, but the mechanistic insight of this process is lacking. Methods and Results-When macrophages were fed apoptotic cells or treated with pitavastatin in vitro, efferocytosisrelated signaling and phagocytic capacity were upregulated in an ERK5 activity-dependent manner. Macrophages isolated from macrophage-specific ERK5-null mice exhibited reduced efferocytosis and levels of gene and protein expression of efferocytosis-related molecules. When these mice were crossed with low-density lipoprotein receptor?/? mice and fed a high-cholesterol diet, atherosclerotic plaque formation was accelerated, and the plaques had more advanced and vulnerable morphology. Conclusions-Our results demonstrate that ERK5, which is robustly activated by statins, is a hub molecule that upregulates macrophage efferocytosis, thereby suppressing atherosclerotic plaque formation. Molecules that upregulate ERK5 and its signaling in macrophages may be good drug targets for suppressing cardiovascular diseases.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 180-191 |
| Number of pages | 12 |
| Journal | Circulation |
| Volume | 130 |
| Issue number | 2 |
| DOIs | |
| State | Published - Jul 8 2014 |
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Keywords
- Atherosclerosis
- Signal transduction
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Physiology (medical)
Cite this
ERK5 activation in macrophages promotes efferocytosis and inhibits atherosclerosis. / Heo, Kyung Sun; Cushman, Hannah J.; Akaike, Masashi; Woo, Chang Hoon; Wang, Xin; Qiu, Xing; Fujiwara, Keigi; Abe, Jun Ichi.
In: Circulation, Vol. 130, No. 2, 08.07.2014, p. 180-191.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - ERK5 activation in macrophages promotes efferocytosis and inhibits atherosclerosis
AU - Heo, Kyung Sun
AU - Cushman, Hannah J.
AU - Akaike, Masashi
AU - Woo, Chang Hoon
AU - Wang, Xin
AU - Qiu, Xing
AU - Fujiwara, Keigi
AU - Abe, Jun Ichi
PY - 2014/7/8
Y1 - 2014/7/8
N2 - Background-Efferocytosis is a process by which dead and dying cells are removed by phagocytic cells. Efferocytosis by macrophages is thought to curb the progression of atherosclerosis, but the mechanistic insight of this process is lacking. Methods and Results-When macrophages were fed apoptotic cells or treated with pitavastatin in vitro, efferocytosisrelated signaling and phagocytic capacity were upregulated in an ERK5 activity-dependent manner. Macrophages isolated from macrophage-specific ERK5-null mice exhibited reduced efferocytosis and levels of gene and protein expression of efferocytosis-related molecules. When these mice were crossed with low-density lipoprotein receptor?/? mice and fed a high-cholesterol diet, atherosclerotic plaque formation was accelerated, and the plaques had more advanced and vulnerable morphology. Conclusions-Our results demonstrate that ERK5, which is robustly activated by statins, is a hub molecule that upregulates macrophage efferocytosis, thereby suppressing atherosclerotic plaque formation. Molecules that upregulate ERK5 and its signaling in macrophages may be good drug targets for suppressing cardiovascular diseases.
AB - Background-Efferocytosis is a process by which dead and dying cells are removed by phagocytic cells. Efferocytosis by macrophages is thought to curb the progression of atherosclerosis, but the mechanistic insight of this process is lacking. Methods and Results-When macrophages were fed apoptotic cells or treated with pitavastatin in vitro, efferocytosisrelated signaling and phagocytic capacity were upregulated in an ERK5 activity-dependent manner. Macrophages isolated from macrophage-specific ERK5-null mice exhibited reduced efferocytosis and levels of gene and protein expression of efferocytosis-related molecules. When these mice were crossed with low-density lipoprotein receptor?/? mice and fed a high-cholesterol diet, atherosclerotic plaque formation was accelerated, and the plaques had more advanced and vulnerable morphology. Conclusions-Our results demonstrate that ERK5, which is robustly activated by statins, is a hub molecule that upregulates macrophage efferocytosis, thereby suppressing atherosclerotic plaque formation. Molecules that upregulate ERK5 and its signaling in macrophages may be good drug targets for suppressing cardiovascular diseases.
KW - Atherosclerosis
KW - Signal transduction
UR - http://www.scopus.com/inward/record.url?scp=84904066609&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84904066609&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.113.005991
DO - 10.1161/CIRCULATIONAHA.113.005991
M3 - Article
C2 - 25001623
AN - SCOPUS:84904066609
VL - 130
SP - 180
EP - 191
JO - Circulation
JF - Circulation
SN - 0009-7322
IS - 2
ER -