Identification of structural features of ursolic acid required to protect monocytes against metabolic stress‐induced dysfunction (249.5)

Abstract

We showed that ursolic acid (UA), a pentacyclic triterpenoid with anti‐inflammatory properties, reduces atherosclerotic lesion size and improves kidney function in diabetic mice. We proposed that the atheroprotective effects of UA are due to its ability to protect monocytes against metabolic stress‐induced dysfunction or “priming”, i.e. the Nox4‐mediated hyper‐responsiveness to chemokine‐induced cell adhesion and migration. The aim of this study was to test eight of UA’s naturally occurring structural analogs and identify the structural features of UA required to inhibit monocyte priming. We determined in metabolically primed THP‐1 monocytes the doses (0.03 ‐ 3 μM) at which UA and its analogues blocked metabolic stress‐induced Nox4 induction and accelerated chemotaxis in response to MCP‐1. Only the UA analogs uvaol and corosolic acid protected monocytes against metabolic priming. We found that altering the position of one methyl group in position 19 of UA abolishes its protective effects. Furthermore, the carboxyl group in position 17 appears to be critical but not sufficient for UA to prevent monocyte priming by metabolic stress. In summary, our data suggest a highly selective molecular mechanism for the protective effects of UA on monocyte priming and dysfunction and UA’s anti‐atherogenic properties. Identifying the functional groups responsible for UA’s beneficial effects will allow us to develop more potent, low‐cost dietary supplements for the prevention of atherosclerosis and other monocyte‐mediated diabetic complications.Grant Funding Source: Supported by grants to RA from the NIH (R01‐AT006885)