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Journal of Lipid Research, Vol. 47, 1762-1770, August 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Antihypertensive action of 2-hydroxyoleic acid in SHRs via modulation of the protein kinase A pathway and Rho kinase

Regina Alemany^1,2,*, Oliver Vögler^1,*, Silvia Terés^*, Carolina Egea^*, Carmela Baamonde^*, Francisca Barceló^*, Carlos Delgado, Karl H. Jakobs and Pablo V. Escribá^*

^* Laboratory of Molecular and Cellular Biomedicine, Department of Biology, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), University of the Balearic Islands, Palma de Mallorca, Spain
Coronary and Postoperative Unit, Policlínica Miramar, Palma de Mallorca, Spain
Institut für Pharmakologie, Universitätsklinikum Essen, Essen, Germany

Published, JLR Papers in Press, May 10, 2006.

¹ R. Alemany and O. Vögler contributed equally to this work.

² To whom correspondence should be addressed. e-mail: regina.alemany{at}uib.es

Olive oil consumption leads to high monounsaturated fatty acid intake, especially oleic acid, and has been associated with a reduced risk of hypertension. However, the molecular mechanisms and contribution of its different components to lower blood pressure (BP) require further evaluation. Here, we examined whether a synthetic, non-ß-oxidation-metabolizable derivative of oleic acid, 2-hydroxyoleic acid (2-OHOA), can normalize BP in adult spontaneously hypertensive rats (SHRs) and whether its antihypertensive action involves cAMP-dependent protein kinase A (PKA) and Rho kinase, two major regulators of vascular smooth muscle contraction. Oral administration of 2-OHOA to SHRs induced sustained systolic BP decreases in a time-dependent (1–7 days) and dose-dependent (100–900 mg/kg every 12 h) manner. After 7 days of treatment with 2-OHOA (600 mg/kg), the systolic BP of SHRs was similar to that of normotensive Wistar Kyoto rats, returning to its initial hypertensive level after withdrawal of 2-OHOA. This treatment strongly increased the protein expression of the catalytic and regulatory RI and RII PKA subunits as well as PKA activity in aortas from SHRs. Consistently, administration of the PKA inhibitor 8-bromo adenosine-3',5'-cyclic monophosphorothioate, Rp isomer, to 2-OHOA-treated SHRs induced a pronounced reversal (up to 59%) of the antihypertensive effect of 2-OHOA. Additionally, 2-OHOA completely reversed the pathological overexpression of aortic Rho kinase found in SHRs, suppressing the vasoconstrictory Rho kinase pathway.

Supplementary key words aorta • fatty acids • hypertension • signal transduction • cAMP-dependent protein kinases • spontaneously hypertensive rats

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