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

J Lipid Res. 2006 Aug;47(8):1762-70. doi: 10.1194/jlr.M500520-JLR200. Epub 2006 May 10.

Abstract

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-beta-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 RIalpha and RIIalpha 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylyl Cyclases / metabolism
  • Animals
  • Antihypertensive Agents / pharmacology
  • Aorta / drug effects
  • Aorta / metabolism
  • Blood Pressure / drug effects
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Dose-Response Relationship, Drug
  • Enzyme Activation / drug effects
  • Immunoblotting
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Oleic Acids / pharmacology*
  • Protein Kinase Inhibitors / pharmacology
  • Protein-Serine-Threonine Kinases / metabolism*
  • Rats
  • Rats, Inbred SHR
  • Rats, Inbred WKY
  • Signal Transduction / drug effects
  • rho-Associated Kinases

Substances

  • 2-hydroxyoleic acid
  • Antihypertensive Agents
  • Intracellular Signaling Peptides and Proteins
  • Oleic Acids
  • Protein Kinase Inhibitors
  • Protein-Serine-Threonine Kinases
  • rho-Associated Kinases
  • Cyclic AMP-Dependent Protein Kinases
  • Adenylyl Cyclases