| As a multi-factorial disease, although experts have proposed many hypothesis, for instance,"endothelium injuries","lipid infiltration","inflammation injury reaction","thrombus formation" to explain its mechanism, they all confirmed that arterial intimal injury by various risk factors is the primary step of AS, which could lead to endothelium dysfunction and damage of the integrity. Therefore, the protection of vascular endothelial plays a positive role in the prevention and treatment of AS. Wen-Xin Decoction (WXD), which is the representative decoction of the treatment by warming yang supplementing heart and promoting blood circulation resolving phlegm (WSPR), has been created by Prof. Hongxin Cao (China Academy of Traditional Chinese Medicine) and used mainly for the clinical treatment of coronary heart disease. WSPR can significantly relieve coronary artery spasm, reduce plaque formation, increase myocardial oxygen supply, and improve heart function. However, it is not yet know whether WSPR has any roles in protecting blood vessel endothelium. This study encloses the mechanism of protection of vascular endothelial from multi-dimension of lipid metabolism, immune response, by using treatment of WSPR as the intervening method. Moreover, it provides experimental evidence for clinical study.Objective:To investigate the protective effects WSPR on vascular endothelial and explore the potential mechanism of WSPR in the treatment of atherosclerosis.Methods:The rat model of atherosclerosis was generated by intraperitoneal injection of vitamin D3in a dose of150,000IU monthly for consecutive3months, and followed by high cholesterol diet alone for2months. The rats were randomly divided into6groups:control group, model group, WXD groups (high, medium and low doses) and atorvastatin group. The rats with atherosclerosis were treated by WXD or atorvastatin for4weeks. We analyzed the ultrastructure of vascular endothelial cells and measured the expressions of PI3K/AKT/eNOS and iNOS in the thoracic aorta tissue. Histopathological changes in the rat aorta were examined by H&E staining. Biochemical tests and ELISA were used to observe the blood lipid and the serum content of ET-1, NO and Ang II. Western Blot and real-time PCR were used to detect the protein and mRNA expressions of iNOS. We also measured the expressions of ICAM-1, VCAM-1, E-selectin and CD68in the thoracic aorta tissue by immunohistochemical.Results:Compared with the model group, the model plus WXD and atorvastatin groups showed a visible reduction of pathological changes. Compared with the model group, serum LDL-C, CHO, TG, AI value and AngⅡ were significant decrease. Our results indicate that WXF increased the Nitric oxide (NO) level, modulated the NO/ET-1ratio, and promoted the injured vascular endothelium repair in a dose-dependent manner. Compared with atorvastatin, high-dose WXD not only has equivalent function in regulating NO/ET-1ratio, but can also increase NO concentration within the physiological range to prevent endothelial damage caused by excessive NO expression. Real-time PCR and Western blot showed that WXD significantly up-regulated PI3Kp85, AKT and eNOS mRNA and protein levels and significantly increased AKT and eNOS phosphorylation. The protein and mRNA expressions of iNOS were down-regulated in the middle and high dosage group of WXD and atorvastatin group, but there was no significant difference among the different treatment groups. The protein expressions of ICAM-1, VCAM-1, E-selectin and CD68were also down-regulated in the middle and high dosage group of WXD and atorvastatin group.Conclusion:WSPR could ameliorate dysfunction of the vascular endothelium and has an obviously therapeutic effect on atherosclerosis. WSPR protects and maintains the integrity of normal vascular endothelial function via activating PI3K/AKT/eNOS pathway, reducing the expression of iNOS and promoting the release of physiological concentration of NO. WSPR could also ameliorate dysfunction of the vascular endothelium via reducing the expression of ICAM-1, VCAM-1, E-selectin and CD68. |
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