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Calcification of Vascular Smooth Muscle Cells and Imaging of Aortic Calcification and Inflammation
Published on: May 31, 2016
Smooth muscle-specific HuR knockout attenuates vascular calcification
Ang Chen1, Peidong Yuan1, Yue Lu1
1State Key Laboratory for Innovation and Transformation of Luobing Theory; Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province; Department of Cardiology, Qilu Hospital of Shandong University, Jinan 250012, China.
Insights
Human antigen R (HuR) promotes vascular calcification by stabilizing Runt-related transcription factor 2 (Runx2) mRNA. Inhibiting HuR or its smooth muscle-specific knockout protects against this condition.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Vascular Biology
Background:
- Vascular calcification is a prevalent pathological feature in atherosclerosis, chronic kidney disease, and aging.
- Human antigen R (HuR), an RNA-binding protein, is implicated in various diseases, but its role in vascular calcification is not well understood.
Purpose of the Study:
- To investigate the function of HuR in vascular calcification.
- To elucidate the molecular mechanisms by which HuR regulates vascular calcification.
Main Methods:
- Generation of smooth muscle-specific HuR knockout (HuRSMKO) mice.
- Assessment of vascular calcification in vitro using vascular smooth muscle cells (VSMCs) and in vivo in mice.
- Analysis of HuR expression regulation by high phosphate via ATF4.
- Investigation of HuR's interaction with Runx2 mRNA.
Main Results:
- HuR expression is upregulated under calcifying conditions, induced by high phosphate via ATF4.
- HuR overexpression exacerbates high phosphate-induced VSMC calcification, while HuR deficiency inhibits it.
- Smooth muscle-specific knockout of HuR and treatment with a HuR inhibitor (CMLD-2) attenuated vascular calcification in vivo.
- HuR directly binds to Runx2 mRNA, enhancing its stability and protein expression.
Conclusions:
- HuR plays a critical role in regulating vascular calcification.
- HuR facilitates vascular calcification through posttranscriptional control of Runx2.
- Targeting HuR represents a potential therapeutic strategy for vascular calcification.
Abstract:
Vascular calcification is a common pathological feature of atherosclerosis, chronic kidney disease, vascular injury and aging. Human antigen R (HuR), a widely expressed RNA-binding protein, plays a key role in the regulation of homeostasis and pathological conditions such as cancer and cardiovascular disease, but its role in vascular calcification remains unclear. In this study, we generated smooth muscle-specific HuR knockout (HuRSMKO) mice to investigate the function of HuR in vascular calcification. The HuR level increased under calcifying conditions, and high phosphate levels increased HuR expression via activating transcription factor 4 (ATF4). HuR overexpression exacerbated high phosphate-induced calcification, whereas HuR deficiency inhibited high phosphate-induced calcification in VSMCs. Smooth muscle-specific knockout of HuR protected against vascular calcification in vivo. Additionally, treatment with the HuR inhibitor CMLD-2 significantly attenuated calcification in mice. Mechanistically, HuR binds directly to Runt-related transcription factor 2 (Runx2) mRNA, increasing its stability and protein expression, which facilitates vascular calcification. These findings demonstrate that HuR plays a critical role in the regulation of vascular calcification through the posttranscriptional control of Runx2.
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