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How Oleic Acid in Olive Oil Reduces Blood Pressure.

How Oleic Acid in Olive Oil Reduces Blood Pressure. Pablo V. Escribá, University of the Balearic Islands, pablo.escriba@uib.es John E. Halver, University of Washington halver@u.washington.edu. CROSS-TALK. AC. AMP c. GMP c. AMP c. REGULATION OF BLOOD PRESSURE. VASCULAR SMOOTH MUSCLE.

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How Oleic Acid in Olive Oil Reduces Blood Pressure.

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  1. How Oleic Acid in Olive Oil Reduces Blood Pressure. Pablo V. Escribá, University of the Balearic Islands, pablo.escriba@uib.es John E. Halver, University of Washington halver@u.washington.edu

  2. CROSS-TALK AC AMPc GMPc AMPc REGULATION OF BLOOD PRESSURE VASCULAR SMOOTH MUSCLE PKA MUSCULAR RELAXATION VASODILATION G proteins PKG Endothelium-dependent PKA

  3. GPCR-associated signaling GPCR-associated signaling Blood Pressure is tightly controlled by several signaling systems. Many of them involve regulation of cell functions through G protein-coupled receptors (GPCRs). This slide shows a Gq protein-associated pathway involved in the regulation of cytosolic Ca2+. How Oleic Acid in olive oil reduces blood pressure. P.V. Escribá & J.E. Halver

  4. G proteins: peripheral membrane proteins G proteins propagate messages from membrane receptors to effectors that control cytosolic levels of second messengers (cAMP, cGMP, IP3, DAG, ions, etc.). Lipid-protein interactions regulate the localization and activity of G proteins and, therefore, cell signaling. How Oleic Acid in olive oil reduces blood pressure. P.V. Escribá & J.E. Halver

  5. G PROTEIN-COUPLED RECEPTORS (GPCRs) INVOLVED IN THE REGULATION OF BP CENTRAL NERVOUS SYSTEM :ADRENOCEPTORSα 2A α2B • PERIPHERAL NERVOUS SYSTEM : CARDIAC MUSCLE: ADRENOCEPTORS α1 β1 β2 MUSCARINIC RECEPTORS M2 SMOOTH MUSCLE: ADRENOCEPTORS α1 β2 MUSCARINIC RECEPTORS M3

  6. CARDIAC CELL SIGNALING 1 adrenoceptor Muscarinic M2 1 adrenoceptor Gs protein Gq11 protein Gi/Go proteins (+) Adenylyl cyclase (+) Phospholipase C (-) Adenylyl cyclase (+) K+ Channels cAMP DAG IP3 (+) Ca2+ (+) PKA (+) PKC Cell hyperpolarization (+) Ca2+ channels contractility contractility contractility

  7. VASCULAR CELL SIGNALING 1 adrenoceptor Muscarinic M3 2 adrenoceptor Nitric Oxide Gs protein Gq11 protein (+) Guanylyl cyclase (+) Adenylyl cyclase (+) Phospholipase C cGMP cAMP DAG IP3 (+) PKG (+) Ca2+ (+) PKA (+) PKC Intracellular Ca2+ Intracellular Ca2+ vasoconstriction Vasorelaxation Vasorelaxation

  8. Membrane lipid structure and G protein-membrane interactions Binding of G proteins to model membranes (liposomes) determined by immunoblotting • G protein heterotrimers prefer nonlamellar-prone membrane regions • G protein a-monomers prefer lamellar-prone regions (higher PC content) How Oleic Acid in olive oil reduces blood pressure. P.V. Escribá & J.E. Halver

  9. Membrane lipid structure and G protein-membrane interactions • G protein bg-dimers have a huge preference for nonlamellar-prone membrane regions (higher PE content). • They take G protein a-monomers from nearby GPCRs. Binding of G proteins to model membranes (liposomes) determined by immunoblotting How Oleic Acid in olive oil reduces blood pressure. P.V. Escribá & J.E. Halver

  10. X-ray analysis DSC analysis FTIR analysis Gg protein-membrane interactions Membrane and aqueous phases Only in membrane Gg on membrane structure Membrane on Gg structure • C-terminal region of Gg: Main player in G protein-lipid interactions. • Membrane lipids affect G protein structure and vice versa. How Oleic Acid in olive oil reduces blood pressure. P.V. Escribá & J.E. Halver

  11. A new model of G protein activity based on their interactions with lipids Two views of the same process. From the membrane (above) or from the cytosol (right): receptors (R) are activated by agonists (a or AG) in hexagonal phase-prone regions (H), which are loaded with G proteins (G) thanks to Gbg. Upon activation, Ga goes to lamellar-prone regions (L) to regulate the activity of effectors (E, E1). How Oleic Acid in olive oil reduces blood pressure. P.V. Escribá & J.E. Halver

  12. WT MutC1 GFP MutC3 MutC4 Gg2-GFP Nuclei Cells Merge Altered Gg protein distribution after point mutations on the C-terminal region (Gg2-GFP fusion proteins) Gg protein-membrane interactions Cellular localization of Gg protein-GFP constructs by confocal microscopy • C-terminal region of Gg: Main player in G protein-lipid interactions. How Oleic Acid in olive oil reduces blood pressure. P.V. Escribá & J.E. Halver

  13. OA EA SA Membrane fatty acids Oleic Acid Elaidic Acid Stearic Acid 18:1 n-9 cis 18:1 n-9 trans 18:0 How Oleic Acid in olive oil reduces blood pressure. P.V. Escribá & J.E. Halver

  14. DEPE:OA (20:1, mole:mole) DEPE DEPE:EA (20:1, mole:mole) Effect of OA and EA on membrane structure by X-Ray diffraction • Oleic acid but not the structurally related fatty acids, elaidic and stearic acid, regulates membrane lipid structure. How Oleic Acid in olive oil reduces blood pressure. P.V. Escribá & J.E. Halver

  15. Effect of OA and EA on G protein function • Oleic acid but not the structurally related fatty acids, elaidic and stearic acid, regulates G protein function. How Oleic Acid in olive oil reduces blood pressure. P.V. Escribá & J.E. Halver

  16. Acute effects of VOO, TO, and OA on systolic BP Normotensive rats Olive oil also induces short-term reductions of BP. Triolein and oleic acid have similar effects V, vehicle; VOO, virgin olive oil; TO, triolein; OA, oleic acid How Oleic Acid in olive oil reduces blood pressure. P.V. Escribá & J.E. Halver

  17. Chronic effects of OA, elaidic acid and stearic acid on systolic BP Normotensive rats Oleic acid, but not elaidic and stearic acids, induces BP reductions. Oleic acid is the fatty acid present in triolein and the main component of olive oil (70-80%). V, vehicle; OA, oleic acid; EA, elaidic acid; SA, stearic acid How Oleic Acid in olive oil reduces blood pressure. P.V. Escribá & J.E. Halver

  18. Effects of VOO treatment on BP in SHRs Olive oil and oleic acid (OA) reduce BP in hypertensive animals. Elaidic acid (EA) and stearic acid (SA) failed to reduce BP. Hypertensive rats How Oleic Acid in olive oil reduces blood pressure. P.V. Escribá & J.E. Halver

  19. Effects of VOO, TO, and OA treatments on total G protein αi2, αi3 and αq/11 subunits and PKCβ1 levels in aorta Olive oil, triolein and oleic acid regulate Gi and Gq protein levels and those of downstream effectors, such as phospholipase C (PLC). V, vehicle; VOO, virgin olive oil; TO, triolein; OA, oleic acid How Oleic Acid in olive oil reduces blood pressure. P.V. Escribá & J.E. Halver

  20. Correlations between BP reductions (mmHg) and decrease of L-to-HII phase transition temperature (°C; A) or the dose of cis-MUFA (g/kg) administered to animals (B) Treatments: 1, VOO; 2, 2-hydroxyoleic acid; 3, TO; 4; OA; 5, stearic acid; 6; vehicle; 7, elaidic acid; 8, soybean oil. Decrease of BP correlates with the dose of cis-monounsaturated fatty acids (cis-MUFA). Fatty acids, rather than triacylglycerides, are involved in this effect. How Oleic Acid in olive oil reduces blood pressure. P.V. Escribá & J.E. Halver

  21. Consequences for human health Consumption of fats that contain cis-monounsaturated fatty acids (e.g., oleic acid) have positive effects on cardiovascular health, compared with saturated or trans-MUFA fats. Because this effect has structural molecular bases, we can design molecules to regulate BP or reverse other pathological processes. How Oleic Acid in olive oil reduces blood pressure. P.V. Escribá & J.E. Halver

  22. Then, I can control cell functions by regulating membrane lipid structure and composition!!! Sure. You may even design nutritional or pharmaceutical approaches to treat human pathologies!!! How Oleic Acid in olive oil reduces blood pressure. P.V. Escribá & J.E. Halver

  23. Chronic effects of soybean oil, VOO, or TO treatments on systolic BP Olive oil, but not soy oil, reduces blood pressure. Triolein, the main triacylglyceride in olive oil reproduces this effect. VOO is the oil obtained from olives by pressure at room temperature. Normotensive rats V, vehicle; SO, soy oil; VOO, virgin olive oil; TO, triolein How Oleic Acid in olive oil reduces blood pressure. P.V. Escribá & J.E. Halver

  24. OLEIC ACID ANALOGUES FOR TREATMENT OF BLOOD PRESSURE OLEIC ACID ANALOGUES FOR TREATMENT OF BLOOD PRESSURE How Oleic Acid in olive oil reduces blood pressure. P.V. Escribá & J.E. Halver

  25. Rational design of 2-hydroxyoleic acid Rational design of 2-hydroxyoleic acid 2-Hydroxyoleic acid (left) is an oleic acid (center) analog that keeps most structural properties of oleic acid and differs from elaidic acid (pink) in its interaction with membranes (right). How Oleic Acid in olive oil reduces blood pressure. P.V. Escribá & J.E. Halver

  26. 2-Hydroxyoleic acid on BP in hypertensive animals 2-Hydroxyoleic acid on BP in hypertensive animals Effect of olive oil Effects of 2-hydroxyoleic acid (2-OHOA) treatment (600 mg/kg every 12 h) on blood pressure (BP) and heart rate in spontaneously hypertensive rats (SHRs) and Wistar Kyoto (WKY) rats How Oleic Acid in olive oil reduces blood pressure. P.V. Escribá & J.E. Halver

  27. 2-Hydroxyoleic acid on BP in hypertensive animals 2-Hydroxyoleic acid on BP in hypertensive animals Dose-dependent effects of 2-OHOA on systolic BP in SHRs How Oleic Acid in olive oil reduces blood pressure. P.V. Escribá & J.E. Halver

  28. 2OHOA increases elasticity in aorta rings Rat aorta rings were preincubated 1 hour in the presence (2OHOA) or absence (control) of 2-hydroxyoleic acid. Then, the contraction in response to noradrenaline was determined. How Oleic Acid in olive oil reduces blood pressure. P.V. Escribá & J.E. Halver

  29. 2-Hydroxyoleic acid has no cytotoxicity Control Control 2OHOA 2OHOA Lung Aorta Heart Kidney Liver S.I.

  30. cGMP is not involved in the effects of 2-hydroxyoleic acid 8 6 protein) levels in aorta 4 -1 ·mg ** 2 (pmol cGMP 0 WKY WKY SHR SHR veh 2OHOA veh 2OHOA The levels of cGMP in normotensive (WKY) and hypertensive (SHR) rats were unrelated to 2-hydroxyoleic acid effects on BP How Oleic Acid in olive oil reduces blood pressure. P.V. Escribá & J.E. Halver

  31. 2-Hydoxyoleic acid on Gi proteins 48 h 10%FBS OH50 OH100 Serum w/o PDGF Gi3 actin BASAL PDGF Gi3 Serum with PDGF actin 2-Hydroxyoleic acid induces reduced expression of G protein. This effect is PDGF-independent. How Oleic Acid in olive oil reduces blood pressure. P.V. Escribá & J.E. Halver

  32. Effects of 2-hydroxyoleic acid treatment (600 mg/kg every 12 h) for 7 days on protein kinase A (PKA) subunit levels in aortas from SHRs and WKY rats 2-Hydroxyoleic acid regulates the expression of some PKA subunits How Oleic Acid in olive oil reduces blood pressure. P.V. Escribá & J.E. Halver

  33. Effects of 2-hydroxyoleic acid treatment (600 mg/kg every 12 h) for 7 days on adenylyl cyclase (AC) activities in SHRs and WKY rat aortas 2-Hydroxyoleic acid treatments induce restoration of Adenyly cyclase activity in rat aorta. Adenyly cyclase produces cAMP, which in turn regulates PKA. How Oleic Acid in olive oil reduces blood pressure. P.V. Escribá & J.E. Halver

  34. Effects of 2-OHOA treatment (600 mg/kg every 12 h) for 7 days on PKA activity in aortas from SHRs and WKY rats 2-Hydroxyoleic acid treatments induce restoration of PKA activity in aorta of hypertensive rats and do not change PKA activity in normotensive rats. How Oleic Acid in olive oil reduces blood pressure. P.V. Escribá & J.E. Halver

  35. b-Adrenoceptor signaling pathway Epinephrine activates b-adrenoceptors, which in turn activate a Gs protein. Gs proteins activate adenylyl cyclase, that produce cAMP and activate PKA. How Oleic Acid in olive oil reduces blood pressure. P.V. Escribá & J.E. Halver

  36. Effects of acute administration of the PKA inhibitor 8-bromo adenosine-3',5'-cyclic monophosphorothioate, Rp isomer (Rp-8-Br-cAMP), on systolic BP in vehicle-treated (control) and 2-OHOA-treated SHRs The use of a specific PKA inhibitor in rats treated with 2-hydroxyoleic acid reversed the hypotensive effect of this drug. This result demonstrates that the proposed mechanism of the hypotensive effects of 2-hydroxyoleic acid (via Gs protein, adenyly cyclase and PKA) operates in vivo. In normotensive animals (treated and untreated) and hypertensive rats not treated with 2-hydroxyoleic acid, no blood pressure reductions were observed (data not shown), indicating that the effect cannot be attributed to the PKA inhibitor itself. In addition, this effect was time- and concentration-dependent. How Oleic Acid in olive oil reduces blood pressure. P.V. Escribá & J.E. Halver

  37. Effects of withdrawal of 2-OHOA on systolic BP and aortic PKA subunit levels in SHRs After treatments with 2-hydroxyoleic acid, blood pressure started to rise to reach their initial high values about two weeks after the administration of the last dose. This slow recovery of blood pressure indicates that the modification induced by the fatty acid occurs on membrane lipids, whose turnover is slower. How Oleic Acid in olive oil reduces blood pressure. P.V. Escribá & J.E. Halver

  38. Effects of 2-OHOA treatment (600 mg/kg every 12 h) for 7 days on Rho kinase II levels in aortas from SHRs and WKY rats Rho kinase also appeared to be markedly increased in hypertensive rats. Treatment with 2-OHOA reduced the expression of this protein to normal levels. This result indicates that besides PKA, vascular cell’s cytoskeleton is also regulated by this compound. How Oleic Acid in olive oil reduces blood pressure. P.V. Escribá & J.E. Halver

  39. CONCLUSION The CIS structure of Oleic Acid fits neatly into the phospholipid structure of biomembranes, and alters receptor sites on the membrane surface, to regulate blood pressure. Q.E.D. For references see:PNAS 105;13811(208) How Oleic Acid in olive oil reduces blood pressure. P.V. Escribá & J.E. Halver

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