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Background and aims High-fat diet (HFD) is reported to induce atherosclerosis and insulin resistance. Macrophage lipid accumulation has been implicated as key mediators during the development of HFD-induced atherosclerosis. Traditional Chinese formula, which has long been used to improve disorder of glucose and lipid metabolism of patients, is now gradually being used as complementary therapy. This study aimed to investigate the effect of Danhong injection (DHI), a Chinese medicine used for the treatment of coronary artery disease, on atherosclerosis and its underlying mechanisms. Methods and results We observed the effects of DHI on HFD-induced atherosclerosis in a mice model, macrophage lipid accumulation in an ox-LDL-stimulated macrophage model, and the role of PI3K/AKT insulin pathway in the process of DHI ameliorating atherosclerosis. The data demonstrated that DHI attenuated atherosclerosis by ameliorating blood lipids, reducing the atherosclerotic index and atherosclerotic plaque area in HFD-induced atherosclerotic mice, and inhibiting TC levels in an ox-LDL-induced macrophage model. By estimating the levels of serum insulin resistance-related indexes and protein expression of GLUT-4, DHI treatment dramatically inhibited the levels of fasting serum NEFA and fasting serum insulin and promoted the protein expression of GLUT-4 in aortas of the HFD-induced atherosclerotic mice. Moreover, according to the hints provided by microarray-based transcriptional profiling, the results demonstrated that DHI treatment also promoted the activation of PI3K/AKT insulin signaling pathway induced by IRS-1 in aortas of HFD-induced atherosclerotic mice. Furthermore, in an ox-LDL-induced macrophage model, the activation of PI3k/AKT signaling pathway also effectively functioned in the process of DHI inhibiting macrophage lipid accumulation. Conclusions These results highlight that DHI treatment attenuates atherosclerosis and macrophage lipid accumulation by promoting the activation of PI3K/AKT insulin signaling pathway. It provides new insights into the molecular mechanism of DHI and its therapeutic potential in the treatment of atherosclerosis.

Background: Renalase is a protein that can regulate sympathetic nerve activity by metabolizing catecholamines, while redundant catecholamines are thought to contribute to atherosclerosis (As). Catecholamine release can be facilitated by angiotensin (Ang) II by binding to Ang II type 1 (AT1) receptors. Valsartan, a special AT1 antagonist, can dilate blood vessels and reduce blood pressure, but it remained unclear whether valsartan can promote the stability of atherosclerotic plaque by affecting renalase. Objective: This study examined the tissue distribution of renalase in ApoE−/− mice fed with a high-fat diet and the effect of valsartan on expression of renalase. Methods: ApoE−/− mice were fed with a high-fat diet for 13 or 26 weeks. As a control, 10 C57BL mice were fed with a standard chow diet. After 13 weeks on the high-fat diet, the ApoE−/− mice were randomized (10 mice/group) and treated with valsartan, simvastatin, or distilled water (control group) for an additional 13 weeks accompanied by a high-fat diet. Results: Knockout of ApoE caused a dramatic increase in expression of renalase in mice adipose tissue. With the disturbance of lipid metabolism induced by a high-fat diet, renalase expression decreased in the liver. Renalase can be expressed in smooth muscle cells and M2 macrophages in atherosclerotic plaque, and its expression gradually decreases in the fibrous cap during the transition from stable to vulnerable atherosclerotic plaque. Valsartan, an AT1 receptor antagonist, promotes the stabilization of atherosclerotic plaque by increasing the levels of renalase in serum and the expression of renalase in the fibrous cap of atherosclerotic plaque. It also reduces triglyceride levels in serum and increases the expression of renalase in the liver. Conclusions: Renalase may be a potential-related gene of lipid metabolism and As, and it may be the possible molecular target of valsartan to help stabilize atherosclerotic plaque.

Lipid metabolism dysregulation plays a crucial role in the occurrence of atherosclerosis (As). SCAP/SREBP signaling is the main pathway for regulating lipid metabolism. Tetramethylpyrazine (TMP), a Traditional Chinese Medicine (TCM) for treating angina pectoris, has antiatherosclerotic effects and ameliorates blood lipids disturbance. However, its precise mechanism remains unclear. This study investigated the mechanism of TMP in ameliorating As in mice model. After six weeks of high-fat diet, 30 ApoE−/− mice were randomized (n = 10) and treated with Lipitor, TMP, or distilled water for six weeks. The serum blood lipids and insulin levels were measured. The expressions of PAQR3, Insig-1, SCAP, SREBP-1c, IRS-1, PI3K, Akt, and mTORC-1 in the adipose tissues were determined. The results showed that TMP could significantly decrease blood lipids levels, insulin, and corrected plaque area of the ApoE−/− mice as compared to the untreated mice (P < 0.05, P < 0.01). Moreover, TMP could significantly downregulate the expressions of SCAP, SREBP-1c, PAQR3, IRS-1, PI3K, Akt, and mTORC1 (P < 0.01). Thus, TMP may ameliorate lipid metabolism disorder and As by downregulating PAQR3 and inhibiting SCAP/SREBP-1c signaling pathway. In addition, PI3K/Akt/mTORC1 signaling pathway may be involved in this process.

Shen-Yuan-Dan Capsule (SYDC), a Chinese medicine used for treating angina pectoris, has anti-atherosclerotic effects in ApoE-deficient (ApoE-/-) mice. Autophagy and aberrant DNA methylation are indispensable in the pathogenesis of atherosclerosis. This study aimed to explore the methylation

Compound Chuanxiong Capsule (CCC), a Chinese herbal compound, can exhibit antiatherosclerotic effect; however, its mechanism is still unclear. This study is designed to study the mechanism of CCC on atherosclerosis in the ApoE-knockout (ApoE−/−) mice fed with a high-fat diet. After 6 weeks of high-fat feeding, 40 ApoE−/−mice were randomized (n=10) and treated with lipitor, high-dose or low-dose CCC, or distilled water (ApoE−/−group) for 7 weeks. The blood lipids in serum and the plaque areas of the mice were measured and the mRNA expressions of phosphatidylinositol-3-kinases (PI3K), Akt, nuclear factor-kappa B (NF-κB), tumor necrosis factor-α(TNF-α), and interleukin-6 (IL-6) of the aortae were determined. The data showed that CCC can significantly decrease the levels of blood lipids, atherosclerosis index, and plaque areas and increase collagen proportion in plaques as compared with the untreated mice (p<0.05,p<0.01). In addition, CCC can significantly reduce the mRNA expressions of PI3K, Akt, NF-κB, IL-6, and TNF-αin the mice fed with a high-fat diet (p<0.001). Thus, we concluded that CCC can inhibit inflammatory reaction in the ApoE−/−mice fed with a high-fat diet. This mechanism may be attributed to regulating PI3K/Akt/NF-κB signaling pathway.

Lipid metabolism dysregulation plays a crucial role in the occurrence of atherosclerosis (As). SCAP/SREBP signaling is the main pathway for regulating lipid metabolism. Tetramethylpyrazine (TMP), a Traditional Chinese Medicine (TCM) for treating angina pectoris, has antiatherosclerotic effects and ameliorates blood lipids disturbance. However, its precise mechanism remains unclear. This study investigated the mechanism of TMP in ameliorating As in mice model. After six weeks of high-fat diet, 30 ApoE−/−mice were randomized (n=10) and treated with Lipitor, TMP, or distilled water for six weeks. The serum blood lipids and insulin levels were measured. The expressions of PAQR3, Insig-1, SCAP, SREBP-1c, IRS-1, PI3K, Akt, and mTORC-1 in the adipose tissues were determined. The results showed that TMP could significantly decrease blood lipids levels, insulin, and corrected plaque area of the ApoE−/−mice as compared to the untreated mice (P<0.05,P<0.01). Moreover, TMP could significantly downregulate the expressions of SCAP, SREBP-1c, PAQR3, IRS-1, PI3K, Akt, and mTORC1 (P<0.01). Thus, TMP may ameliorate lipid metabolism disorder and As by downregulating PAQR3 and inhibiting SCAP/SREBP-1c signaling pathway. In addition, PI3K/Akt/mTORC1 signaling pathway may be involved in this process.