TY - JOUR
T1 - Runx2 (Runt-Related Transcription Factor 2)-Mediated Microcalcification Is a Novel Pathological Characteristic and Potential Mediator of Abdominal Aortic Aneurysm
AU - Li, Zhiqing
AU - Zhao, Zuoquan
AU - Cai, Zeyu
AU - Sun, Yong
AU - Li, Li
AU - Yao, Fang
AU - Yang, Liu
AU - Zhou, Yuan
AU - Zhu, Haibo
AU - Fu, Yi
AU - Wang, Li
AU - Fang, Wei
AU - Chen, Yabing
AU - Kong, Wei
N1 - Publisher Copyright:
© 2020 Lippincott Williams and Wilkins. All rights reserved.
PY - 2020/5/1
Y1 - 2020/5/1
N2 - Objective: Abdominal aortic aneurysms (AAAs) are highly lethal diseases without effective clinical predictors and therapeutic targets. Vascular microcalcification, as detected by fluorine-18-sodium fluoride, has recently been recognized as a valuable indicator in predicting atherosclerotic plaque rupture and AAA expansion. However, whether vascular microcalcification involved in the pathogenesis of AAA remains elusive. Approach and Results: Microcalcification was analyzed in human aneurysmal aortas histologically and in AngII (angiotensin II)-infused ApoE-/-mouse aortas by fluorine-18-sodium fluoride positron emission tomography and X-ray computed tomography scanning in chronological order in live animals. AAA patients' aortic tissue showed markedly enhanced microcalcification in the aortic media within the area proximal to elastic fiber degradation, compared with non-AAA patients. Enhanced fluorine-18-sodium fluoride uptake preceded significant aortic expansion in mice. Microcalcification-positive mice on day 7 of AngII infusion showed dramatic aortic expansion on subsequent days 14 to 28, whereas microcalcification-negative AngII-infused mice and saline-induced mice did not develop AAA. The application of hydroxyapatite, the main component of microcalcification, aggravated AngII-induced AAA formation in vivo. RNA-sequencing analysis of the suprarenal aortas of 4-day-AngII-infused ApoE-/-mice and bioinformatics analysis with ChIP-Atlas database identified the potential involvement of the osteogenic transcriptional factor Runx2 (runt-related transcription factor 2) in AAA. Consistently, vascular smooth muscle cell-specific Runx2 deficiency markedly repressed AngII-induced AAA formation in the ApoE-/-mice compared with the control littermates. Conclusions: Our studies have revealed microcalcification as a novel pathological characteristic and potential mediator of AAA, and targeting microcalcification may represent a promising strategy for AAA prevention and treatment.
AB - Objective: Abdominal aortic aneurysms (AAAs) are highly lethal diseases without effective clinical predictors and therapeutic targets. Vascular microcalcification, as detected by fluorine-18-sodium fluoride, has recently been recognized as a valuable indicator in predicting atherosclerotic plaque rupture and AAA expansion. However, whether vascular microcalcification involved in the pathogenesis of AAA remains elusive. Approach and Results: Microcalcification was analyzed in human aneurysmal aortas histologically and in AngII (angiotensin II)-infused ApoE-/-mouse aortas by fluorine-18-sodium fluoride positron emission tomography and X-ray computed tomography scanning in chronological order in live animals. AAA patients' aortic tissue showed markedly enhanced microcalcification in the aortic media within the area proximal to elastic fiber degradation, compared with non-AAA patients. Enhanced fluorine-18-sodium fluoride uptake preceded significant aortic expansion in mice. Microcalcification-positive mice on day 7 of AngII infusion showed dramatic aortic expansion on subsequent days 14 to 28, whereas microcalcification-negative AngII-infused mice and saline-induced mice did not develop AAA. The application of hydroxyapatite, the main component of microcalcification, aggravated AngII-induced AAA formation in vivo. RNA-sequencing analysis of the suprarenal aortas of 4-day-AngII-infused ApoE-/-mice and bioinformatics analysis with ChIP-Atlas database identified the potential involvement of the osteogenic transcriptional factor Runx2 (runt-related transcription factor 2) in AAA. Consistently, vascular smooth muscle cell-specific Runx2 deficiency markedly repressed AngII-induced AAA formation in the ApoE-/-mice compared with the control littermates. Conclusions: Our studies have revealed microcalcification as a novel pathological characteristic and potential mediator of AAA, and targeting microcalcification may represent a promising strategy for AAA prevention and treatment.
KW - abdominal aortic aneurysm
KW - calcification
KW - core binding factor alpha 1 subunit
KW - positron emission tomography
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U2 - 10.1161/ATVBAHA.119.314113
DO - 10.1161/ATVBAHA.119.314113
M3 - Article
C2 - 32212850
AN - SCOPUS:85083902503
SN - 1079-5642
VL - 40
SP - 1352
EP - 1369
JO - Arteriosclerosis, thrombosis, and vascular biology
JF - Arteriosclerosis, thrombosis, and vascular biology
IS - 5
ER -