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Biochemical, Molecular, and Genetic Mechanisms

Oleanolic Acid Induces Prostacyclin Release in Human Vascular Smooth Muscle Cells through a Cyclooxygenase-2-Dependent Mechanism^1,2

³ Centro de Investigación Cardiovascular, Consejo Superior de Investigaciones Científicas/Institut Català de Ciències Cardiovasculars-Hospital de la Santa Creu i Sant Pau, Barcelona, Spain and ⁴ Instituto de la Grasa, CSIC, Sevilla, Spain

^* To whom correspondence should be addressed. E-mail: jmartinez{at}csic-iccc.org.

Oleanolic acid is a triterpenoid that may contribute to the cardio-protective effects of olive oil. Our goal was to assess whether oleanolic acid could modulate eicosanoid biosynthesis and to determine the mechanism involved in this effect. Human coronary smooth muscle cells (SMC) were treated with oleanolic acid, erythrodiol, or hydroxytyrosol and eicosanoid release was measured by enzyme immunoassay. Cyclooxygenase (Cox)-1 and Cox-2 protein and messenger sRNA levels were analyzed by Western blot and real-time PCR, respectively. Mitogen-activated protein kinase (MAPK) pathways were assessed using specific antibodies. Oleanolic acid induced prostaglandin I₂ (PGI₂) release by human coronary SMC, an effect that was prevented by celecoxib (a specific inhibitor of Cox-2). The increased PGI₂ was time-and dose-dependent and was associated to the u-regulation of Cox-2. No effects were observed on thromboxane A₂. Erythrodiol but not hydroxytyrosol upregulated Cox-2 expression and induced PGI₂ synthesis. Oleanolic acid induced an early phosphorylation of p38 MAPK and p42/44 MAPK but not c-Jun N-terminal kinase-1 (JNK-1). SB203580 (p38MAPK inhibitor) and U0126 (MAPK kinase1/2 inhibitor) abrogated the upregulation of Cox-2 and PGI₂ release induced by oleanolic acid. A peptide inhibitor of JNK-1 (L-JNKI1) did not produce any effect. The induction of Cox-2 was preceded by an early activation of cAMP regulatory element-binding protein, a key transcription factor involved in Cox-2 transcriptional upregulation. Therefore, oleanolic acid contributes to vascular homeostasis by inducing PGI₂ release in a Cox-2-dependent manner. Oleanolic acid could be regarded as a bioactive molecule that may contribute to the beneficial effects of the Mediterranean diet.