TY - JOUR
T1 - Astrocytic Lrp4 (Low-density lipoprotein receptor–related protein 4) contributes to ischemia-induced brain injury by regulating ATP release and adenosine-A2AR (Adenosine A2A Receptor) signaling
AU - Ye, Xin Chun
AU - Hu, Jin Xia
AU - Li, Lei
AU - Li, Qiang
AU - Tang, Fulei
AU - Lin, Sen
AU - Sun, Dong
AU - Sun, Xiang Dong
AU - Cui, Gui Yun
AU - Mei, Lin
AU - Xiong, Wencheng
N1 - Funding Information:
This study is supported in part by grants from the National Institutes of Health (AG045781 and AG051773 to Dr Xiong and NS082007, NS090083, AG051510, and MH083317 to Dr Mei), US Department of Veterans Affairs (to Dr Xiong and Dr Mei), National Natural Science Foundation of China (81571155 to Dr Ye and 81571210 to Dr Cui), Natural Science Foundation of the Higher Education Institutions of Jiangsu Province (17KJB320017), and Jiangsu Provincial Medical Youth Talent (QNRC2016788).
Publisher Copyright:
© 2017 American Heart Association, Inc.
PY - 2018
Y1 - 2018
N2 - Background and Purpose—Lrp4 (low-density lipoprotein receptor–related protein 4) is predominantly expressed in astrocytes, where it regulates glutamatergic neurotransmission by suppressing ATP release. Here, we investigated Lrp4’s function in ischemia/stroke-induced brain injury response, which includes glutamate-induced neuronal death and reactive astrogliosis. Methods—The brain-specific Lrp4 conditional knockout mice (Lrp4GFAP-Cre), astrocytic-specific Lrp4 conditional knockout mice (Lrp4GFAP-creER), and their control mice (Lrp4f/f) were subjected to photothrombotic ischemia and the transient middle cerebral artery occlusion. After ischemia/stroke, mice or their brain samples were subjected to behavior tests, brain histology, immunofluorescence staining, Western blot, and quantitative real-time polymerase chain reaction. In addition, primary astrocytes and neurons were cocultured with or without oxygen and glucose deprivation and in the presence or absence of the antagonist for adenosine-A2AR (adenosine A2A receptor) or ATP-P2X7R (P2X purinoceptor 7) signaling. Gliotransmitters, such as glutamate, d-serine, ATP, and adenosine, in the condition medium of cultured astrocytes were also measured. Results—Lrp4, largely expressed in astrocytes, was increased in response to ischemia/stroke. Both Lrp4GFAP-Cre and Lrp4GFAP-creER mice showed less brain injury, including reduced neuronal death, and impaired reactive astrogliosis. Mechanistically, Lrp4 conditional knockout in astrocytes increased ATP release and the production of ATP derivative, adenosine, which were further elevated by oxygen and glucose deprivation. Pharmacological inhibition of ATP-P2X7R or adenosine-A2AR signaling diminished Lrp4GFAP-creER’s protective effect. Conclusions—The astrocytic Lrp4 plays an important role in ischemic brain injury response. Lrp4 deficiency in astrocytes seems to be protective in response to ischemic brain injury, likely because of the increased ATP release and adenosine-A2AR signaling.
AB - Background and Purpose—Lrp4 (low-density lipoprotein receptor–related protein 4) is predominantly expressed in astrocytes, where it regulates glutamatergic neurotransmission by suppressing ATP release. Here, we investigated Lrp4’s function in ischemia/stroke-induced brain injury response, which includes glutamate-induced neuronal death and reactive astrogliosis. Methods—The brain-specific Lrp4 conditional knockout mice (Lrp4GFAP-Cre), astrocytic-specific Lrp4 conditional knockout mice (Lrp4GFAP-creER), and their control mice (Lrp4f/f) were subjected to photothrombotic ischemia and the transient middle cerebral artery occlusion. After ischemia/stroke, mice or their brain samples were subjected to behavior tests, brain histology, immunofluorescence staining, Western blot, and quantitative real-time polymerase chain reaction. In addition, primary astrocytes and neurons were cocultured with or without oxygen and glucose deprivation and in the presence or absence of the antagonist for adenosine-A2AR (adenosine A2A receptor) or ATP-P2X7R (P2X purinoceptor 7) signaling. Gliotransmitters, such as glutamate, d-serine, ATP, and adenosine, in the condition medium of cultured astrocytes were also measured. Results—Lrp4, largely expressed in astrocytes, was increased in response to ischemia/stroke. Both Lrp4GFAP-Cre and Lrp4GFAP-creER mice showed less brain injury, including reduced neuronal death, and impaired reactive astrogliosis. Mechanistically, Lrp4 conditional knockout in astrocytes increased ATP release and the production of ATP derivative, adenosine, which were further elevated by oxygen and glucose deprivation. Pharmacological inhibition of ATP-P2X7R or adenosine-A2AR signaling diminished Lrp4GFAP-creER’s protective effect. Conclusions—The astrocytic Lrp4 plays an important role in ischemic brain injury response. Lrp4 deficiency in astrocytes seems to be protective in response to ischemic brain injury, likely because of the increased ATP release and adenosine-A2AR signaling.
KW - A2A
KW - Adenosine
KW - Adenosine
KW - Astrocytes
KW - Brain injury
KW - Ischemia
KW - Receptor
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U2 - 10.1161/STROKEAHA.117.018115
DO - 10.1161/STROKEAHA.117.018115
M3 - Article
C2 - 29212737
AN - SCOPUS:85043713817
SN - 0039-2499
VL - 49
SP - 165
EP - 174
JO - Stroke
JF - Stroke
IS - 1
ER -