TY - JOUR
T1 - Reduced Nhe1 (Na+-H+Exchanger-1) Function Protects ApoE-Deficient Mice from Ang II (Angiotensin II)-Induced Abdominal Aortic Aneurysms
AU - Liu, Cong Lin
AU - Liu, Xin
AU - Wang, Yunzhe
AU - Deng, Zhiyong
AU - Liu, Tianxiao
AU - Sukhova, Galina K.
AU - Wojtkiewicz, Gregory R.
AU - Tang, Rui
AU - Zhang, Jin Ying
AU - Achilefu, Samuel
AU - Nahrendorf, Matthias
AU - Libby, Peter
AU - Wang, Xiaofang
AU - Shi, Guo Ping
N1 - Funding Information:
This study is supported by grants from the National Heart, Lung, and Blood Institute (HL139598 to M. Nahrendorf; HL123568, HL60942, and AG063839 to G.-P. Shi, HL080472 and HL134892 to P. Libby) and the RRM Charitable Fund (to P. Libby). J.-Y. Zhang was funded by the National Natural Science Foundation of China (81570274 and 81870328), the University-College Joint Cultivation Fund of Zhengzhou University (2016_BSTDJJ-19), and the Henan Thousand Talents Program (ZYQR201912131).
Publisher Copyright:
© 2020 Lippincott Williams and Wilkins. All rights reserved.
PY - 2020/7/1
Y1 - 2020/7/1
N2 - IgE-mediated activation of Nhe1 (Na+-H+exchanger-1) induces aortic cell extracellular acidification and promotes cell apoptosis. A pH-sensitive probe pHrodo identified acidic regions at positions of macrophage accumulation, IgE expression, and cell apoptosis in human and mouse abdominal aortic aneurysm (AAA) lesions. Ang II (angiotensin II)-induced AAA in Nhe1-insufficient Apoe-/-Nhe1+/-mice and Apoe-/-Nhe1+/+littermates tested Nhe1 activity in experimental AAA, because Nhe1-/-mice develop ataxia and epileptic-like seizures and die early. Nhe1 insufficiency reduced AAA incidence and size, lesion macrophage and T-cell accumulation, collagen deposition, elastin fragmentation, cell apoptosis, smooth muscle cell loss, and MMP (matrix metalloproteinase) activity. Nhe1 insufficiency also reduced blood pressure and the plasma apoptosis marker TCTP (translationally controlled tumor protein) but did not affect plasma IgE. While pHrodo localized the acidic regions to macrophage clusters, IgE expression, and cell apoptosis in AAA lesions from Apoe-/-Nhe1+/+mice, such acidic areas were much smaller in lesions from Apoe-/-Nhe1+/-mice. Nhe1-FcϵR1 colocalization in macrophages from AAA lesions support a role of IgE-mediated Nhe1 activation. Gelatin zymography, immunoblot, and real-time polymerase chain reaction analyses demonstrated that Nhe1 insufficiency reduced the MMP activity, cysteinyl cathepsin expression, IgE-induced apoptosis, and NF-κB activation in macrophages and blocked IgE-induced adhesion molecule expression in endothelial cells. A near-infrared fluorescent probe (LS662) together with fluorescence reflectance imaging of intact aortas showed reduced acidity in AAA lesions from Nhe-1-insufficient mice. This study revealed extracellular acidity at regions rich in macrophages, IgE expression, and cell apoptosis in human and mouse AAA lesions and established a direct role of Nhe1 in AAA pathogenesis.
AB - IgE-mediated activation of Nhe1 (Na+-H+exchanger-1) induces aortic cell extracellular acidification and promotes cell apoptosis. A pH-sensitive probe pHrodo identified acidic regions at positions of macrophage accumulation, IgE expression, and cell apoptosis in human and mouse abdominal aortic aneurysm (AAA) lesions. Ang II (angiotensin II)-induced AAA in Nhe1-insufficient Apoe-/-Nhe1+/-mice and Apoe-/-Nhe1+/+littermates tested Nhe1 activity in experimental AAA, because Nhe1-/-mice develop ataxia and epileptic-like seizures and die early. Nhe1 insufficiency reduced AAA incidence and size, lesion macrophage and T-cell accumulation, collagen deposition, elastin fragmentation, cell apoptosis, smooth muscle cell loss, and MMP (matrix metalloproteinase) activity. Nhe1 insufficiency also reduced blood pressure and the plasma apoptosis marker TCTP (translationally controlled tumor protein) but did not affect plasma IgE. While pHrodo localized the acidic regions to macrophage clusters, IgE expression, and cell apoptosis in AAA lesions from Apoe-/-Nhe1+/+mice, such acidic areas were much smaller in lesions from Apoe-/-Nhe1+/-mice. Nhe1-FcϵR1 colocalization in macrophages from AAA lesions support a role of IgE-mediated Nhe1 activation. Gelatin zymography, immunoblot, and real-time polymerase chain reaction analyses demonstrated that Nhe1 insufficiency reduced the MMP activity, cysteinyl cathepsin expression, IgE-induced apoptosis, and NF-κB activation in macrophages and blocked IgE-induced adhesion molecule expression in endothelial cells. A near-infrared fluorescent probe (LS662) together with fluorescence reflectance imaging of intact aortas showed reduced acidity in AAA lesions from Nhe-1-insufficient mice. This study revealed extracellular acidity at regions rich in macrophages, IgE expression, and cell apoptosis in human and mouse AAA lesions and established a direct role of Nhe1 in AAA pathogenesis.
KW - abdominal aortic aneurysm
KW - cathepsins
KW - endothelial cells
KW - fluorescent dye
KW - mast cell
UR - http://www.scopus.com/inward/record.url?scp=85086345907&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85086345907&partnerID=8YFLogxK
U2 - 10.1161/HYPERTENSIONAHA.119.14485
DO - 10.1161/HYPERTENSIONAHA.119.14485
M3 - Article
C2 - 32475310
AN - SCOPUS:85086345907
SN - 0194-911X
VL - 76
SP - 87
EP - 100
JO - Hypertension
JF - Hypertension
IS - 1
ER -