Rosmarinic Acid Inhibits Platelet Aggregation and Neointimal Hyperplasia In Vivo and Vascular Smooth Muscle Cell Dedifferentiation, Proliferation, and Migration In Vitro via Activation of the Keap1-Nrf2-ARE Antioxidant System

• Published in: Journal of agricultural and food chemistry 2022-06, Vol.70 (24), p.7420-7440
• Main Authors: Chen, Chen, Ma, Jiulong, Xu, Zhiping, Chen, Liang, Sun, Bo, Shi, Yan, Miao, Yujia, Wu, Tianlong, Qin, Meng, Zhang, Yang, Zhang, Ming, Cao, Xia
• Format: Article
• Language: English
• Subjects: Antioxidant Response Elements; Antioxidants - metabolism; Antioxidants - pharmacology; Becaplermin - pharmacology; Bioactive Constituents, Metabolites, and Functions; Cell Dedifferentiation; Cell Movement; Cell Proliferation; Cells, Cultured; Cinnamates; Depsides; Humans; Hyperplasia - metabolism; Hyperplasia - pathology; Kelch-Like ECH-Associated Protein 1 - genetics; Kelch-Like ECH-Associated Protein 1 - metabolism; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neointima - metabolism; Neointima - pathology; Neointima - prevention & control; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Platelet Aggregation; Rosmarinic Acid; Vascular Remodeling
• ISSN: 0021-8561; 1520-5118
• DOI: 10.1021/acs.jafc.2c01176

The activation of platelets and proliferation of vascular smooth muscle cells (VSMCs) in the vascular intima play an essential role in the pathological mechanism of vascular restenosis (RS). Rosmarinic acid (RA) is a natural phenolic acid compound. However, its mechanism of action on platelets and VSMCs is still unclear. This study investigated the effects of RA on platelet function, VSMCs phenotypic conversion, proliferation, and migration in vascular remodeling with a specific focus on the Keap1-Nrf2-ARE signaling pathway. RA inhibited platelet aggregation and Ca2+ release and significantly reduced the release of platelet microvesicles. In addition, RA inhibited the phenotypic transition of VSMCs in vitro and in vivo. In vitro experiments showed that RA could effectively inhibit the proliferation and migration of VSMCs induced by the platelet-derived growth factor (PDGF)-BB. PDGF-BB triggered ROS generation and a decrease in mitochondrial membrane potential, which were inhibited by RA. Mechanistically, after artery injury or treatment with PDGF-BB, VSMCs presented with inhibition of the Nrf2/antioxidant response element (ARE) signaling pathway. RA treatment reversed this profile by activating the Nrf2/ARE signaling pathway; stabilizing Keap1 protein; upregulating HO-1, NQO1, GCLM, and GST protein levels; promoting typical Nrf2 nuclear translocation; and preventing VSMCs from oxidative stress damage. On the other hand, RA also inhibited the NF-κB pathway to reduce inflammation. In summary, these results indicate that RA inhibits platelet function and attenuates the proliferation, migration, and phenotypic transition of VSMCs induced by PDGF-BB in vitro and vascular remodeling in vivo. Therefore, RA treatment may be a potential therapy for preventing or treating RS.