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Inhibition of Orai1 Store–Operated Calcium Channel Prevents Foam Cell Formation and Atherosclerosis
- Source :
- Arteriosclerosis, Thrombosis, and Vascular Biology. 36:618-628
- Publication Year :
- 2016
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2016.
-
Abstract
- Objective— To determine the role of orai1 store–operated Ca 2+ entry in foam cell formation and atherogenesis. Approach and Results— Acute administration of oxidized low-density lipoprotein (oxLDL) activates an orai1-dependent Ca 2+ entry in macrophages. Chelation of intracellular Ca 2+ , inhibition of orai1 store–operated Ca 2+ entry, or knockdown of orai1 dramatically inhibited oxLDL-induced upregulation of scavenger receptor A, uptake of modified LDL, and foam cell formation. Orai1-dependent Ca 2+ entry induces scavenger receptor A expression and foam cell formation through activation of calcineurin but not calmodulin kinase II. Activation of nuclear factor of activated T cells is not involved in calcineurin signaling to foam cell formation. However, oxLDL dephosohorylates and activates apoptosis signal–regulating kinase 1 in macrophages. Orai1 knockdown prevents oxLDL-induced apoptosis signal–regulating kinase 1 activation. Knockdown of apoptosis signal–regulating kinase 1, or inhibition of its downstream effectors, JNK and p38 mitogen-activated protein kinase, reduces scavenger receptor A expression and foam cell formation. Notably, orai1 expression is increased in atherosclerotic plaques of apolipoprotein E −/− mice fed with high-cholesterol diet. Knockdown of orai1 with adenovirus harboring orai1 siRNA or inhibition of orai1 Ca 2+ entry with SKF96365 for 4 weeks dramatically inhibits atherosclerotic plaque development in high-cholesterol diet feeding apolipoprotein E −/− mice. In addition, inhibition of orai1 Ca 2+ entry prevents macrophage apoptosis in atherosclerotic plaque. Moreover, the expression of inflammatory genes in atherosclerotic lesions and the infiltration of myeloid cells into the aortic sinus plaques are decreased after blocking orai1 signaling. Conclusions— Orai1-dependent Ca 2+ entry promotes atherogenesis possibly by promoting foam cell formation and vascular inflammation, rendering orai1 Ca 2+ channel a potential therapeutic target against atherosclerosis.
- Subjects :
- 0301 basic medicine
Time Factors
ORAI1 Protein
p38 mitogen-activated protein kinases
Aortic Diseases
Apoptosis
030204 cardiovascular system & hematology
Biology
MAP Kinase Kinase Kinase 5
Transfection
p38 Mitogen-Activated Protein Kinases
03 medical and health sciences
Apolipoproteins E
0302 clinical medicine
Cell Line, Tumor
Ca2+/calmodulin-dependent protein kinase
Animals
Humans
Calcium Signaling
Scavenger receptor
Protein kinase A
Aorta
Calcium Chelating Agents
Foam cell
Mice, Knockout
Dose-Response Relationship, Drug
Voltage-dependent calcium channel
Anticholesteremic Agents
Calcineurin
JNK Mitogen-Activated Protein Kinases
Scavenger Receptors, Class A
Atherosclerosis
Calcium Channel Blockers
Plaque, Atherosclerotic
Cell biology
Lipoproteins, LDL
Disease Models, Animal
Cholesterol
030104 developmental biology
Biochemistry
Macrophages, Peritoneal
Calcium
RNA Interference
Calcium Channels
Inflammation Mediators
Cardiology and Cardiovascular Medicine
Foam Cells
Subjects
Details
- ISSN :
- 15244636 and 10795642
- Volume :
- 36
- Database :
- OpenAIRE
- Journal :
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Accession number :
- edsair.doi.dedup.....f7f6a0a9fa7dc448e7bb707682649e49