3-Arylcoumarin inhibits vascular calcification by inhibiting the generation of AGEs and anti-oxidative stress

Abstract

Objective

This work aims to screen drugs for preventing and treating vascular calcification. Method: We screened a series of 3-arylcoumarins for the detection of vascular calcification-associated factors using human aortic vascular smooth muscle cells.

Results

We found that compounds 14 and 32 significantly inhibited alkaline phosphatase (ALP) activity similar to aminoguanidine hydrochloride (AGH) in a cellular model of AGEs-induced calcification. We also found that compounds 14 and 32 could significantly decrease the levels of factors such as AGEs, intracellular calcium ions, and total ROS in the calcified cell model. Further study indicates that compound 14 could significantly inhibit the expression of P-ERK1/2, PKC, NF-κB, RAGE and OPN proteins and increased the expression of SM22-α and PPAR-γ proteins in the calcified cells.

Conclusion

We speculate that compound 14 inhibits vascular calcification by inhibiting oxidative stress and inhibiting AGEs production, suggesting that 3-arylcoumarin derivatives are potential candidates for the treatment of vascular calcification.

Novelty Statement

Vascular calcification is a process similar to bone formation, which is highly adjustable and active. Currently, there are no specific drugs to delay or reverse vascular calcification. Through the screening of 44 coumarin compounds synthesised by our group, compound 14 was obtained to dose-dependently inhibit the calcification of vascular smooth muscle cells without affecting the normal proliferation of cells, decreasing the intracellular calcium concentration, inhibiting the activity of ALP enzyme. In conclusion, the calcium lowering effect of compound 14 is a potential candidate for drugs for the treatment of vascular calcification.

Keywords:

• 3-arylcoumarin derivatives
• vascular calcification
• AGEs
• oxidative stress

Acknowledgement

Research and development of hypoglycaemic and cardiovascular protective activities of a 3-arylcoumarin compound and its derivatives (ZR202011020095). Thanks to Dr. Zhaozhong Zhong and Dr. Xiaodong Mou for editing this paper.

Ethical statement

Animal Studies: This study only participated in part of the mouse tissue staining study, and no patient participated in its human tissue study, which conformed to ethical standards.

Disclosure statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Neither the funding agency nor any outside organisation has participated in the study design or has any competing interest.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This work was supported by the Academic promotion program of Shandong First Medical University (No. 2019LJ003).