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

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1352-1369
Number of pages18
JournalArteriosclerosis, thrombosis, and vascular biology
Volume40
Issue number5
DOIs
StatePublished - May 1 2020
Externally publishedYes

Keywords

  • abdominal aortic aneurysm
  • calcification
  • core binding factor alpha 1 subunit
  • positron emission tomography

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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