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Theranostics 2023; 13(4):1325-1341. doi:10.7150/thno.80250 This issue Cite

Research Paper

GLSP and GLSP-derived triterpenes attenuate atherosclerosis and aortic calcification by stimulating ABCA1/G1-mediated macrophage cholesterol efflux and inactivating RUNX2-mediated VSMC osteogenesis

Guobin Zheng^3#, Yun Zhao^1,2#, Zhenhao Li^5#, Yunqing Hua^1,2, Jing Zhang^1,2, Yaodong Miao⁶, Yang Guo², Lan Li^1,2, Jia Shi^1,2, Zhengwei Dong^1,2, Shu Yang^4✉, Guanwei Fan^1,2✉, Chuanrui Ma^1,2✉

1. First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
2. National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
3. NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
4. Department of Geriatrics, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen, China
5. Zhejiang ShouXianGu Botanical Drug Institute, Zhejiang Hangzhou 321200 China
6. Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, P. R. China
#These authors contributed equally to this article.

✉ Corresponding authors: Chuanrui Ma, PhD; Guanwei Fan, PhD; Shu Yang, PhD. First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion. No.88, Chang Ling Road, Li Qi Zhuang Jie, Xi Qing District, Tianjin, P.R. China; E-mail: chuanruima2013nankai.edu.cn; guanwei.fanedu.cn; yang.shucom More

Abstract

Background and Purpose: Atherosclerosis is the main pathophysiological foundation of cardiovascular disease, which was caused by inflammation and lipid metabolism disorder, along with vascular calcification. Aortic calcification leads to reduced plaque stability and eventually causes plaque rupture which leads to cardiovascular events. Presently, the drug to treat aortic calcification remains not to be available. Ganoderma lucidum spore powder (GLSP) is from Ganoderma lucidum which is a Traditional Chinese Medicine with the homology of medicine and food. It has multiple pharmacological effects, but no research on aortic calcification during atherosclerosis was performed. This study investigated the effects of GLSP on atherosclerosis and aortic calcification and revealed the underlying mechanism.

Methods: In vivo, 8-week-aged male LDLR^-/- mice were fed a high-fat diet to induce atherosclerosis along with aortic calcification. Simultaneously, the mice were treated with GLSP at the first week of HFD feeding to determine the protection against early and advanced atherosclerosis. Subsequently, the mice tissues were collected to evaluate the effects of GLSP on atherosclerosis, and aortic calcification, and to reveal the underlying mechanism. In vitro, we determined the major components of GLSP triterpenes by HPLC, and subsequently assessed the protective effects of these main active components on lipid metabolism, inflammation, and calcification in RAW264.7 and HASMC cells.

Results: We observed GLSP attenuated plaque area and aortic calcification in the mice with early and advanced atherosclerosis. GLSP reduced the number of foam cells by improving ABCA1/G1-mediated cholesterol efflux in macrophages. In addition, GLSP protected against the aortic endothelium activation. Moreover, GLSP inhibited aortic calcification by inactivating RUNX2-mediated osteogenesis in HASMCs. Furthermore, we determined the major components of GLSP triterpenes, including Ganoderic acid A, Ganoderic acid B, Ganoderic acid C6, Ganoderic acid G, and Ganodermanontriol, and found that these triterpenes promoted ABCA1/G1-mediated cholesterol efflux and inhibited inflammation in macrophage, and inactivated RUNX2-mediated osteogenesis in VSMC.

Conclusions: This study demonstrates that GLSP attenuates atherosclerosis and aortic calcification by improving ABCA1/G1-mediated cholesterol efflux and inactivating RUNX2-mediated osteogenesis in LDLR^-/- mice. GLSP may be a potential drug candidate for the treatment of atherosclerosis and vascular calcification.

Keywords: GLSP, triterpenes, atherosclerosis, aortic calcification, cholesterol metabolism

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