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Updated: May 28, 2026
Calcification of Vascular Smooth Muscle Cells and Imaging of Aortic Calcification and Inflammation
Published on: May 31, 2016
YAK577 Attenuates Vascular Calcification by Targeting an MMP14-NOX2/ROS Axis in VSMCs and a Vitamin D3-Induced Mouse
Hongyan Zhou1,2, Hae Jin Kee1,2,3, Seong Min Jeong1,2
1Heart Research Center, Chonnam National University Hospital, Gwangju 61469, Republic of Korea.
Abstract:
Vascular calcification is an actively regulated process driven by vascular smooth muscle cell (VSMC) osteogenic reprogramming and promoted by oxidative stress and extracellular matrix remodeling. We investigated whether the novel histone deacetylase inhibitor YAK577 mitigates calcification by modulating an MMP14-NOX2/ROS-associated pathway in calcification medium (CM)-treated VSMCs and a vitamin D3-induced arterial calcification model in 8-week-old male C57BL/6N mice. Calcification was assessed by Alizarin Red S/von Kossa staining and calcium quantification; osteogenic markers (BMP2, RUNX2, MSX2) and MMPs were examined by qRT-PCR and immunoblotting; intracellular ROS was measured by DHE staining with N-acetylcysteine as an antioxidant control; and MMP14 was manipulated by siRNA knockdown or plasmid overexpression. YAK577 was non-cytotoxic at effective concentrations and reduced CM-induced calcium deposition and osteogenic marker expression. YAK577 reduced MMP14 expression and suppressed CM-induced NOX2/p47phox activation and ROS accumulation, while GSK2795039 attenuated CM-induced DHE fluorescence. MMP14 silencing attenuated, whereas MMP14 overexpression enhanced, osteogenic signaling and increased NOX2. In vivo, YAK577 reduced vitamin D3-induced aortic calcium burden, histological calcification, and the expression of MMP14, NOX2, and osteogenic markers. These data support a working model in which YAK577 alleviates vascular calcification, at least in part, by suppressing an MMP14-associated NOX2/p47phox-ROS axis.
Insights
The novel drug YAK577 reduces vascular calcification by inhibiting the MMP14-NOX2/ROS pathway. This histone deacetylase inhibitor lessens calcium buildup and osteogenic markers in cells and mice.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Pharmacology
Background:
- Vascular calcification involves VSMC osteogenic reprogramming, oxidative stress, and matrix remodeling.
- Histone deacetylase inhibitors are explored for therapeutic potential in vascular diseases.
Purpose of the Study:
- To investigate if the histone deacetylase inhibitor YAK577 mitigates vascular calcification.
- To elucidate the role of the MMP14-NOX2/ROS pathway in YAK577's mechanism of action.
Main Methods:
- Utilized VSMCs treated with calcification medium (CM) and a vitamin D3-induced mouse model.
- Assessed calcification via staining and calcium quantification; analyzed gene and protein expression (osteogenic markers, MMPs, NOX2).
- Measured intracellular ROS and manipulated MMP14 levels using siRNA and overexpression.
Main Results:
- YAK577 reduced CM-induced calcium deposition and osteogenic marker expression in VSMCs.
- YAK577 suppressed MMP14, NOX2 activation, and ROS accumulation, while MMP14 manipulation affected osteogenic signaling.
- In vivo, YAK577 decreased aortic calcification and expression of MMP14, NOX2, and osteogenic markers.
Conclusions:
- YAK577 alleviates vascular calcification by suppressing the MMP14-associated NOX2/p47phox-ROS axis.
- YAK577 demonstrates therapeutic potential for treating vascular calcification.
