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Updated: Oct 10, 2025
Isolation and Characterization of Primary Rat Valve Interstitial Cells: A New Model to Study Aortic Valve Calcification
Published on: November 20, 2017
Metformin alleviates the calcification of aortic valve interstitial cells through activating the PI3K/AKT pathway in
Qiao En1, Huang Zeping1, Wang Yuetang1
1Department of Structural Heart Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences, Peking Union Medical College, 167 Beilishi Road, Xicheng District, Beijing, 100037, China.
Background:
Calcific aortic valve disease (CAVD) is the most prevalent valvular disease worldwide. However, no effective treatment could delay or prevent the progression of the disease due to the poor understanding of its pathological mechanism. Many studies showed that metformin exerted beneficial effects on multiple cardiovascular diseases by mediating multiple proteins such as AMPK, NF-κB, and AKT. This study aims to verify whether metformin can inhibit aortic calcification through the PI3K/AKT signaling pathway.
Methods:
We first analyzed four microarray datasets to screen differentially expressed genes (DEGs) and signaling pathways related to CAVD. Then aortic valve samples were used to verify selected genes and pathways through immunohistochemistry (IHC) and western blot (WB) assays. Aortic valve interstitial cells (AVICs) were isolated from non-calcific aortic valves and then cultured with phosphate medium (PM) with or without metformin to verify whether metformin can inhibit the osteogenic differentiation and calcification of AVICs. Finally, we used inhibitors and siRNA targeting AMPK, NF-κB, and AKT to study the mechanism of metformin.
Results:
We screened 227 DEGs; NF-κB and PI3K/AKT signaling pathways were implicated in the pathological mechanism of CAVD. IHC and WB experiments showed decreased AMPK and AKT and increased Bax in calcific aortic valves. PM treatment significantly reduced AMPK and PI3K/AKT signaling pathways, promoted Bax/Bcl2 ratio, and induced AVICs calcification. Metformin treatment ameliorated AVICs calcification and apoptosis by activating the PI3K/AKT signaling pathway. AMPK activation and NF-κB inhibition could inhibit AVICs calcification induced by PM treatment; however, AMPK and AKT inhibition reversed the protective effect of metformin.
Conclusions:
This study, for the first time, demonstrates that metformin can inhibit AVICs in vitro calcification by activating the PI3K/AKT signaling pathway; this suggests that metformin may provide a potential target for the treatment of CAVD. And the PI3K/AKT signaling pathway emerges as an important regulatory axis in the pathological mechanism of CAVD.
Insights
Metformin inhibits calcific aortic valve disease (CAVD) progression by activating the PI3K/AKT pathway. This research identifies a potential therapeutic target for CAVD, a common heart valve condition.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Pharmacology
Background:
- Calcific aortic valve disease (CAVD) is the most common valvular heart disease globally.
- Current treatments for CAVD are limited due to an incomplete understanding of its pathological mechanisms.
- Metformin has shown promise in cardiovascular diseases by modulating key proteins like AMPK, NF-κB, and AKT.
Purpose of the Study:
- To investigate the potential of metformin in inhibiting aortic calcification.
- To elucidate the role of the PI3K/AKT signaling pathway in metformin's effects on CAVD.
Main Methods:
- Analysis of microarray datasets to identify differentially expressed genes and pathways in CAVD.
- Immunohistochemistry (IHC) and Western Blot (WB) assays on aortic valve samples.
- In vitro studies using aortic valve interstitial cells (AVICs) treated with metformin and pathway-specific inhibitors/siRNA.
Main Results:
- Microarray analysis identified NF-κB and PI3K/AKT pathways in CAVD pathogenesis.
- Metformin treatment ameliorated AVIC calcification and apoptosis by activating the PI3K/AKT pathway.
- AMPK activation and NF-κB inhibition suppressed PM-induced AVIC calcification, while AMPK/AKT inhibition reversed metformin's protective effects.
Conclusions:
- Metformin inhibits in vitro calcification of AVICs via activation of the PI3K/AKT signaling pathway.
- The PI3K/AKT pathway is a critical regulator in CAVD pathogenesis.
- Metformin presents a potential therapeutic strategy for CAVD treatment.
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