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Background and Aim: The phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin complex 1 (mTORC1) signaling pathway plays a crucial role in autophagy and inflammation. Our previous studies demonstrated that Shen-Yuan-Dan Capsule (SYDC), a Chinese medicine used for treating angina pectoris, has anti-atherosclerotic and anti-inflammatory effects in mice. However, its effects on autophagy and the PI3K/Akt/mTORC1 signaling pathway remain unclear. This study aimed to explore the effects of SYDC on autophagy and PI3K/Akt/mTORC1 signaling in the apolipoprotein E knockout (ApoE−/−) mouse model and in macrophage-derived foam cells to delineate the underlying mechanism. Methods: After 6 weeks of high-fat diet, ApoE–/– mice were randomly grouped into control, Lipitor, low-SYDC (SYDC-L), middle-SYDC (SYDC-M), and high-SYDC (SYDC-H) groups (n = 10). The mice were intragastrically administered the respective treatment for 6 weeks. Murine RAW264.7 cells were stimulated with oxidized low-density lipoprotein (ox-LDL) (80 µg/ml) for 24 h and then pretreated with SYDC freeze-dried powder for another 24 h. Cells treated with SYDC were co-cultured for 24 h with LY294002, tricirbine, and rapamycin to investigate the effects on the PI3K/Akt/mTORC1 signaling pathway. Results: SYDC ameliorated blood lipid levels, reduced the atherosclerotic index and plaque areas in the aortic root in mice, and inhibited total cholesterol (TC) levels and cholinesterase (ChE)/TC ratios in ox-LDL stimulated macrophages. Moreover, SYDC up-regulated Beclin1 and LC3II/I proteins in mice and in the ox-LDL–stimulated macrophages. Moreover, SYDC inhibited AKT phosphorylation at Ser473 and mTOR phosphorylation at Ser2448 in mice and in ox-LDL–stimulated macrophages. Furthermore, SYDC's inhibitory of ChE/TC ratios in ox-LDL–stimulated macrophages was not changed by selective inhibition of the PI3K/Akt/mTORC1 pathway. Conclusions: Our results highlight that SYDC treatment attenuates foam cell formation by promoting autophagy via inhibiting activation of the PI3K/Akt/mTORC1 signaling pathway. This study provides new insights into the molecular mechanism underlying SYDC's therapeutic potential for treating atherosclerosis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: Type 2 diabetes is considered a “risk equivalent” for cardiovascular disease, rosiglitazone, as an insulin sensitizer, has been explored as a novel therapeutic drug for the prevention of cardiovascular disease, but whether it can stabilize vulnerable atherosclerotic plaques is still unknown. Our study aims to investigate the effect of rosiglitazone on plaque stability in fat-fed ApoE-knockout mice. Our findings showed that rosiglitazone can stabilize the vulnerable atherosclerotic plaques in fat-fed ApoE-knockout mice by modifying the plaque composition as well as decreasing the number of buried fibrous caps and its anti-inflammatory effect probably is the key mechanism through which promotes the plaque more stable. [Copyright &y& Elsevier]

• Renalase, a newly discovered cytokine, plays an indispensable role in CVD. • Renalase exerts cardioprotective effects by metabolizing catecholamines, reducing myocardial remodelling and inhibiting apoptosis. • Renalase is a potential drug target for clinical treatment of CVD. Cardiovascular disease (CVD) is prevalent worldwide and remains a leading cause of death. Although substantial progress has been made in the diagnosis and treatment of CVD, the prognosis remains unsatisfactory. Renalase is a newly discovered cytokine that is synthesized by the kidney and then secreted into blood. Numerous studies have suggested the efficacy of renalase in treating CVD by metabolizing catecholamines in the circulatory system. As a new biomarker of heart disease, renalase is normally recognized as a signalling molecule that activates cytoprotective intracellular signals to lower blood pressure, protect ischaemic heart muscle and promote atherosclerotic plaque stability in CVD, which subsequently improves cardiac function. Due to its important regulatory role in the circulatory system, renalase has gradually become a potential target in the treatment of CVD. This review summarizes the structure, mechanism and function of renalase in CVD, thereby providing preclinical evidence for alternative approaches and new prospects in the development of renalase-related drugs against CVD. [ABSTRACT FROM AUTHOR]