Antihypertensive activity of oleanolic acid is mediated via downregulation of secretory phospholipase A2 and fatty acid synthase in spontaneously hypertensive rats

• Published in: International journal of molecular medicine Vol. 46; no. 6; pp. 2019 - 2034
• Main Authors: Zhang, Shiming, Liu, Yuecheng, Wang, Xiaoming, Tian, Zhenhua, Qi, Dongmei, Li, Yunlun, Jiang, Haiqiang
• Format: Journal Article
• Language: English
• Published: Greece Spandidos Publications UK Ltd 01.12.2020; D.A. Spandidos
• Subjects: Animals; Antihypertensive Agents - pharmacology; Antihypertensives; Biomarkers - metabolism; Blood pressure; Cardiovascular disease; Cell adhesion & migration; Cholesterol; Coronary vessels; Diastole - drug effects; Discriminant Analysis; Down-Regulation - drug effects; Endothelium; Fatty Acid Synthases - metabolism; Fatty acids; Growth factors; Hypertension; Hypertension - physiopathology; Inflammation; Kinases; Least-Squares Analysis; Lipidomics; Lipids; Lipids - chemistry; Liver; Liver - drug effects; Liver - enzymology; Liver - pathology; Male; Metabolic Networks and Pathways - drug effects; Metabolism; Metabolites; Metabolome - drug effects; Multivariate Analysis; Oleanolic Acid - pharmacology; Oral administration; Phospholipases A2, Secretory - metabolism; Proteins; Rats, Inbred SHR; ROC Curve; Systole - drug effects
• ISSN: 1107-3756; 1791-244X
• DOI: 10.3892/ijmm.2020.4744

Oleanolic acid (OA) is reported to possess antihypertensive activity via the regulation of lipid metabolism; however, the mechanisms underlying lipid regulation by OA are yet to be fully elucidated. The aim of the present study was to evaluate the mechanisms via which OA regulates lipid metabolism in spontaneously hypertensive rats (SHRs) via ultra‑performance liquid chromatography‑quadrupole/Orbitrap‑mass spectrometry (MS)‑based lipidomics analysis. SHRs were treated with OA (1.08 mg/kg) for 4 weeks. The liver tissues were excised, homogenized in dichloromethane and centrifuged, and subsequently the supernatant layer was collected and concentrated under vacuum to dryness. The dichloromethane extract was subjected to MS analysis and database searching, and comparison of standards was performed to identify potential biomarkers. Partial least squares‑discriminant analysis performed on the liver lipidome revealed a total of 14 endogenous metabolites that were significantly changed in the SHR model group (SH group) compared with Wistar Kyoto rats [normal control (NC group)], including glycerophospholipids, sphingolipids and glycerides. Heatmaps revealed that the liver lipid profiles in the OA group were clustered more closely compared with those observed in the NC group, indicating that the antihypertensive effect of OA was mediated via regulation of liver lipid metabolites. It was observed that the protein levels of secretory phospholipase A2 (sPLA2) and fatty acid synthase (FAS) were increased in the SH group compared with the NC group. In addition, the levels of lysophosphatidylcholine and triglycerides in the liver were elevated, whereas the levels of low‑density lipoprotein cholesterol and high‑density lipoprotein cholesterol were reduced in the SH group. Upon treatment with OA, the mRNA and protein levels of PLA2 and FAS were observed to be downregulated. Collectively, the present study indicated that the antihypertensive activity of OA was mediated via downregulation of sPLA2 and FAS in SHRs, and that treatment with OA resulted in significant improvements in blood pressure and associated abnormalities in the lipid metabolites.