Abstract
We showed that ursolic acid (UA), a pentacyclic triterpenoid with anti‐inflammatory properties, reduces atherosclerotic lesion size and monocyte dysfunction in diabetic mice. We proposed that UA protects monocytes against metabolic stress‐induced monocyte dysfunction or “priming,” by preventing the induction of Nox4, the rate‐limiting step promoting hyper‐responsiveness to chemoattractants and accelerated chemotaxis induced by metabolic stress. We have also demonstrated that UA rescues MKP‐1 protein expression and activity in metabolically primed cells. The aim of this study was to investigate nine of UA's naturally occurring analogs and identify the structural features of UA required to inhibit monocyte priming and prevent Nox4 induction. We determined the doses (0.03 ‐ 3 μM) at which UA and its analogs blocked metabolic stress‐induced acceleration of chemotaxis in response to MCP‐1 in metabolically primed THP‐1 monocytes. Only the UA analogs hederagenin (IC50 = 0.64 μM), oleanolic acid (IC50 = 1.9 μM), and uvaol (IC50 = 2.46 μM), protected monocytes against metabolic priming. UA was the most potent analog (IC50 = 0.1 μM). All protective analogs also prevented Nox4 induction and rescued MKP‐1 from degradation. Our data suggests that hederagenin, oleanolic acid and uvaol prevent monocyte priming and dysfunction through the same mechanism as UA and thus may all be atheroprotective. Identifying the structural features responsible for UA's beneficial effects will enable us to develop more potent, dietary supplements for the prevention of atherosclerosis and other monocyte‐mediated diabetic complications.
 
 Funding Source: Supported by a grant to RA from the NIH (R01‐AT006885)
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