دورية أكاديمية
Role of Runx2 in Calcific Aortic Valve Disease in Mouse Models.
| العنوان: | Role of Runx2 in Calcific Aortic Valve Disease in Mouse Models. |
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| المؤلفون: | Dharmarajan S; Department of Bioengineering, University of Washington, Seattle, WA, United States., Speer MY; Department of Bioengineering, University of Washington, Seattle, WA, United States., Pierce K; Department of Bioengineering, University of Washington, Seattle, WA, United States., Lally J; Department of Bioengineering, University of Washington, Seattle, WA, United States., Leaf EM; Department of Bioengineering, University of Washington, Seattle, WA, United States., Lin ME; Department of Bioengineering, University of Washington, Seattle, WA, United States., Scatena M; Department of Bioengineering, University of Washington, Seattle, WA, United States., Giachelli CM; Department of Bioengineering, University of Washington, Seattle, WA, United States. |
| المصدر: | Frontiers in cardiovascular medicine [Front Cardiovasc Med] 2021 Oct 29; Vol. 8, pp. 687210. Date of Electronic Publication: 2021 Oct 29 (Print Publication: 2021). |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Frontiers Media S.A Country of Publication: Switzerland NLM ID: 101653388 Publication Model: eCollection Cited Medium: Print ISSN: 2297-055X (Print) Linking ISSN: 2297055X NLM ISO Abbreviation: Front Cardiovasc Med Subsets: PubMed not MEDLINE |
| أسماء مطبوعة: | Original Publication: Lausanne : Frontiers Media S.A., [2014]- |
| مستخلص: | Background: Calcific aortic valve disease is common in the aging population and is characterized by the histological changes of the aortic valves including extracellular matrix remodeling, osteochondrogenic differentiation, and calcification. Combined, these changes lead to aortic sclerosis, aortic stenosis (AS), and eventually to heart failure. Runt-related transcription factor 2 (Runx2) is a transcription factor highly expressed in the calcified aortic valves. However, its definitive role in the progression of calcific aortic valve disease (CAVD) has not been determined. In this study, we utilized constitutive and transient conditional knockout mouse models to assess the molecular, histological, and functional changes in the aortic valve due to Runx2 depletion. Methods: Lineage tracing studies were performed to determine the provenance of the cells giving rise to Runx2+ osteochondrogenic cells in the aortic valves of LDLr -/- mice. Hyperlipidemic mice with a constitutive or temporal depletion of Runx2 in the activated valvular interstitial cells (aVICs) and sinus wall cells were further investigated. Following feeding with a diabetogenic diet, the mice were examined for changes in gene expression, blood flow dynamics, calcification, and histology. Results: The aVICs and sinus wall cells gave rise to Runx2+ osteochondrogenic cells in diseased mouse aortic valves. The conditional depletion of Runx2 in the SM22α+ aVICs and sinus wall cells led to the decreased osteochondrogenic gene expression in diabetic LDLr -/- mice. The transient conditional depletion of Runx2 in the aVICs and sinus wall cells of LDLr -/- ApoB 100 CAVD mice early in disease led to a significant reduction in the aortic peak velocity, mean velocity, and mean gradient, suggesting the causal role of Runx2 on the progression of AS. Finally, the leaflet hinge and sinus wall calcification were significantly decreased in the aortic valve following the conditional and temporal Runx2 depletion, but no significant effect on the valve cusp calcification or thickness was observed. Conclusions: In the aortic valve disease, Runx2 was expressed early and was required for the osteochondrogenic differentiation of the aVICs and sinus wall cells. The transient depletion of Runx2 in the aVICs and sinus wall cells in a mouse model of CAVD with a high prevalence of hemodynamic valve dysfunction led to an improved aortic valve function. Our studies also suggest that leaflet hinge and sinus wall calcification, even in the absence of significant leaflet cusp calcification, may be sufficient to cause significant valve dysfunctions in mice. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Dharmarajan, Speer, Pierce, Lally, Leaf, Lin, Scatena and Giachelli.) |
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| معلومات مُعتمدة: | R01 HL062329 United States HL NHLBI NIH HHS; R35 HL139602 United States HL NHLBI NIH HHS; R35 HL171342 United States HL NHLBI NIH HHS; R01 HL114611 United States HL NHLBI NIH HHS; R01 HL081785 United States HL NHLBI NIH HHS; P30 DK017047 United States DK NIDDK NIH HHS |
| فهرسة مساهمة: | Keywords: CAVD; RUNX2; aortic valve stenosis; calcification; osteochondrogenic differentiation; valve interstitial cells |
| تواريخ الأحداث: | Date Created: 20211115 Latest Revision: 20240913 |
| رمز التحديث: | 20240913 |
| مُعرف محوري في PubMed: | PMC8585763 |
| DOI: | 10.3389/fcvm.2021.687210 |
| PMID: | 34778386 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2297-055X |
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| DOI: | 10.3389/fcvm.2021.687210 |