Runx2 (Runt-Related Transcription Factor 2)-Mediated Microcalcification Is a Novel Pathological Characteristic and Potential Mediator of Abdominal Aortic Aneurysm

Zhiqing Li; Zuoquan Zhao; Zeyu Cai; Yong Sun; Li Li; Fang Yao; Liu Yang; Yuan Zhou; Haibo Zhu; Yi Fu; Li Wang; Wei Fang; Yabing Chen; Wei Kong

doi:10.1161/ATVBAHA.119.314113

Runx2 (Runt-Related Transcription Factor 2)-Mediated Microcalcification Is a Novel Pathological Characteristic and Potential Mediator of Abdominal Aortic Aneurysm

Arterioscler Thromb Vasc Biol. 2020 May;40(5):1352-1369. doi: 10.1161/ATVBAHA.119.314113. Epub 2020 Mar 26.

Authors

Zhiqing Li¹, Zuoquan Zhao², Zeyu Cai¹, Yong Sun³, Li Li⁴, Fang Yao⁵, Liu Yang¹, Yuan Zhou⁶, Haibo Zhu⁷, Yi Fu¹, Li Wang⁵, Wei Fang², Yabing Chen³, Wei Kong¹

Affiliations

¹ Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, China (Z.L., Z.C., L.Y., Y.F., W.K.).
² Department of Nuclear Medicine (Z.Z., W.F.), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing.
³ Department of Pathology, University of Alabama at Birmingham (Y.S., Y.C.).
⁴ Department of Pathology, State Key Laboratory of Cardiovascular Disease (L.L.), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing.
⁵ State Key Laboratory of Cardiovascular Disease (F.Y., L.W.), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing.
⁶ Department of Biomedical Informatics, School of Basic Medical Sciences, Peking University, Beijing, China (Y.Z.).
⁷ Fuwai Hospital, National Center for Cardiovascular Diseases, and State Key Laboratory for Bioactive Substances and Functions of Natural Medicines, Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica (H.Z.), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing.

PMID: 32212850
DOI: 10.1161/ATVBAHA.119.314113

Abstract

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.

Keywords: abdominal aortic aneurysm; calcification; core binding factor alpha 1 subunit; positron emission tomography.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Angiotensin II
Animals
Aorta, Abdominal / diagnostic imaging
Aorta, Abdominal / metabolism*
Aortic Aneurysm, Abdominal / chemically induced
Aortic Aneurysm, Abdominal / diagnostic imaging
Aortic Aneurysm, Abdominal / genetics
Aortic Aneurysm, Abdominal / metabolism*
Case-Control Studies
Core Binding Factor Alpha 1 Subunit / genetics
Core Binding Factor Alpha 1 Subunit / metabolism*
Dilatation, Pathologic
Disease Models, Animal
Durapatite
Female
Humans
Male
Mice, Inbred C57BL
Mice, Knockout, ApoE
Middle Aged
Signal Transduction
Vascular Calcification / chemically induced
Vascular Calcification / diagnostic imaging
Vascular Calcification / genetics
Vascular Calcification / metabolism*
Vascular Remodeling

Substances

Core Binding Factor Alpha 1 Subunit
RUNX2 protein, human
Runx2 protein, mouse
Angiotensin II
Durapatite