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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

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

slide2

CROSS-TALK

AC

AMPc

GMPc

AMPc

REGULATION OF BLOOD PRESSURE

VASCULAR SMOOTH MUSCLE

PKA

MUSCULAR

RELAXATION

VASODILATION

G proteins

PKG

Endothelium-dependent

PKA

slide3

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

slide4

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

g protein coupled receptors gpcrs involved in the regulation of bp
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

cardiac cell signaling
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

vascular cell signaling
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

membrane lipid structure and g protein membrane interactions

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

membrane lipid structure and g protein membrane interactions1

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

g g protein membrane interactions

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

a new model of g protein activity based on their interactions with lipids

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

g g protein membrane interactions1

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

membrane fatty acids

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

slide14

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

slide15

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

slide16

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

slide17

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

slide18

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

slide19

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

slide20

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

consequences for human health

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

slide22

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

slide23

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

oleic acid analogues for treatment of blood pressure

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

slide25

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

slide26

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

slide27

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

2ohoa increases elasticity in aorta rings
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

slide29

2-Hydroxyoleic acid has no cytotoxicity

Control

Control

2OHOA

2OHOA

Lung

Aorta

Heart

Kidney

Liver

S.I.

slide30

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

slide31

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

slide32

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

slide33

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

slide34

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

slide35

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

slide36

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

slide37

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

slide38

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

conclusion

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