Objective To investigate the mechanism of Xuezhikang Capsules (血脂康胶囊) in intervening coronary microvascular dysfunction (CMD) in ApoE^−/− mice based on non-targeted metabolomics. Methods After seven weeks of high-fat diet feeding, SPF-grade ApoE^−/− mice were injected with sodium laurate via tail vein to establish CMD model. The mice were then randomly divided into model group, atorvastatin (6 mg/kg) group, Xuezhikang low-, medium-, and high-dose (90, 180, 360 mg/kg) groups, another 12 C57BL/6J mice were selected as the control group. After eight weeks of drug intervention, the morphology and pathological changes of myocardial tissue and myocardial microvessels in mice were detected using hematoxylin-eosin (HE), Carstairs and Heidenhain staining. Cardiac functional injury was evaluated by echocardiography. Oil red O staining was used to evaluate the degree of lipid accumulation in the aorta. Lipid levels, myocardial injury and endothelial function-related indicators were detected by biochemical assays, ELISA, immunohistochemistry and immunofluorescence. The changes in fecal metabolites were analyzed using non-targeted metabolomics, and differential metabolites and significantly enriched metabolic pathways were identified. Western blotting was used to detect silent information regulator 1 (SIRT1), peroxisome proliferator activated receptor γ coactivator-1α (PGC-1α), p-p65 and p65 protein expressions in myocardial tissue. Results Compared with model group, Xuezhikang Capsules significantly reduced the levels of triglycerides, total cholesterol, low-density lipoprotein cholesterol, as well as the degree of myocardial and endothelial injury in serum of mice (P < 0.05, 0.01), and significantly improved the degree of microthrombus, myocardial ischemia and heart function decline in mice (P < 0.01). Non-targeted metabolomics identified 14 differentially expressed metabolites and 15 enriched pathways (P < 0.05). Western blotting results showed that compared with model group, Xuezhikang Capsules significantly up-regulated the protein expressions of SIRT1 and PGC-1α in myocardial tissue (P < 0.01), and down-regulated the protein expression of p-p65/p65 (P < 0.01). Conclusion Xuezhikang Capsules could regulate blood lipids, improve endothelial dysfunction and inflammatory response, thereby effectively improving cardiac function and reducing myocardial structural damage in CMD model mice. Its mechanism may be related to the regulation of arginine-proline-α-ketoglutarate metabolic axis and eNOS/SIRT1/PGC-1α signaling pathway.

Xuezhikang Capsules  /  coronary microvascular dysfunction  /  ApoE^-/- mice  /  untargeted metabolomics  /  arginine-proline-α-ketoglutarate metabolic axis  /  eNOS/SIRT1/PGC-1α signaling pathway