Effects of statins beyond hepatic cholesterol synthesis regulation

Effects of statins beyond hepatic cholesterol synthesis regulation:Managing Cardiovascular Risk In the 21st Century

Lina BadimonBarcelona CardiovascularScienceCenter (CSIC-ICCC)

Hospital de la Santa Creui Sant Pau

Málaga, April 2014

Cholesterol and Lipoproteinsin CoronaryArteryDisease

Bloodcholesterol pool•Vesselwalllipid pool•Cellulareffects

Intestinal CholesterolAbsorption

HepaticCholesterolSynthesis

Badimon L. 2014




HepaticCholesterolSynthesis

HYPERCHOLESTEROLEMIA ATHEROSCLEROSIS

Badimon L. 2014




HepaticCholesterolSynthesistreatment

Badimon L. 2014





Badimon L. 2014


bloodcholesterol pool•Vesselwalllipid pool•Cellulareffects



Badimon L. 2014

Ch

an

ge

in

co

ron

ary

art

ery

dia

mete

r (%

)

Acetylcholine dose

10

5

0

-5

-10

-15

10-9M 10-8M 10-7M 10-6M

Placebo

Lovastatin

Treasure CB, et al. N Engl J Med. 1995;332:481-487.

Statin Therapy Improves Endothelial Function

ICCC-Badimon L. 2014

Andrews TC, et al. Circulation. 1997;95:324-328.

Statin Therapy Reduces Myocardial Ischemia

Placebo

(n = 20)

Treatment

(n = 20)24

17

15

10

5

0

Baseline 6 months

24

17

15

10

5

0

Baseline 6 months

Ep

iso

des o

f is

ch

em

ia/4

8 h


Lovastatin

Alonso R et al Atherosclerosis 2001;Martinez J et al ATVB 2001.

Albert MA, et al. JAMA. 2001;Ridker PM, et al. Circulation. 2001;Crea F, et al. Clin Cardiol.2002;Semb AG. JACC 203;Nissen SE, et al. JAMA. 2004;

AlfonJ JTH 1999;Casani JTH 2005;Molins B ATVB 2008;Molins B ATVB 2010

Llorente-Cortés V, et al. Circulation 2004


Padro T,..Badimon L. Cardiovasc Res 2007

agLDL impair migration of human coronary VSMC

VSMC

+ /- agLDL (16 hours)

double sided scrape-wound

0

20

40

60

80

100

0 2 4 6 8 12

Time (hours)

% r

ege

ne

rate

d a

rea

control

agLDL

agLDL

control

8h6h

12h6h

12h0h


0 hours

A

8 hours after wounding

C

nLDL

agLDL

- rosuvastatin

B C

D E

F G

+ rosuvastatin

0

20

40

60

80

100

0 2 4 6 8 12

wo

un

d c

ove

rage

(%

)

C

C+R

nLDL

nLDL+R

C

C+R

agLDL

agLDL+R

0

20

40

60

80

100

wo

un

d c

ove

rage

(%

)

0 2 4 6 8 12

nLDL agLDL

hours hours

STATINS REVERT THE PATHOLOGICAL EFFECTSOF LDL IN THE VESSEL WALL

Pad

roT,

Lu

gan

oR

, Gar

cia

M, B

adim

on

L. P

losO

ne

20

12


PROTEOMIC INVESTIGATION ON STATIN EFFECTS ON HUMAN CORONARY VASCULAR CELLS

Pad

roT,

Lu

gan

oR

, Gar

cia

M, B

adim

on

L. P

losO

ne

20

12


MRLC

MolinsB, Peña E, PadroT, CasaniL, MendietaC, Badimon L. ATVB 2010AHA- KARL LINK AWARD – BEST ARTICLE ON THROMBOSIS OF 2010

platelet surface GRP78 (red) platelet membrane receptor GPIIIa (green).

ControlRestingPlatelets

ControlSheared (1500/s) Platelets

Rosuvastatin-treated Sheared (1500/s) Platelets

GRP78 IN HUMAN PLATELETS

control

Rosuvastatin 8 M

0

2000

4000

6000

8000

10000

12000

250 s-1 1500 s-1

Platelet Adhesion

*

*

MP

D (

m2/f

ield

)

1500 s-1

Urea-soluble fraction(membrane/ cytoskeleton)

Tris-soluble fraction(cytoplasm)

1500 s-1 + rosuvastain

1 2 3

PROTEOMIC IDENTIFICATION OF GRP78


Sardella G, Catheter CardiovascInterv. 2012

ROMA TRIAL: ROSUVASTATIN PRETREATMENT IN ELECTIVE PCI

Statin-naif pts/40mg rosu/24h pre-PCI

P>0.001


Norris DM, Cardiol Rev 2012 Nov 20(6) 319-24

StatinLoadingBeforePercutaneousCoronaryInterventionto Reduce PeriproceduralMyocardialInfarction


HMG-CoA

Mevalonate

Farnesyl-PP

Squalene

Lanosterol

CHOLESTEROL

CAROTENOIDSDOLICHOL

CYP51 (Lanosterol demethylase)

ERG25 (C-4 sterol methyl oxidase)

4,4-dimethyl zymosterol

4-methyl zymosterol-4-carboxilic acid

STATINS

Badimon L. 2014

ESTATINAS

Rho

ROCKRhotekinCitron quinasa

mDIA MLC fosfatasa

Protein-kinase N-related quinasa

Rigidez aórticaPressión sanguínea

IRS-1

Insulin/PI3K/Akt

Hipertrofia cardíacaHipertensiónAngiogénesis

PKB/Akt FOXO

Supervivencia celular

Citoesqueleto de actina(Contracción CML)

Hipertensión pulmonar

Rac1

IRS: sustrato receptor de la insulina

Quinasa activada p21

Proteínas involucradas en el remodelado

del citoesqueleto

Proteinas activadoras de la GTPasa unida a

calmodulina

Proteínas síndrome Wiskott-

Aldrich Producción superóxido

P67 phox

↑NADPH oxidasa

ROS

Acetil CoA

HMG-CoA

Mevalonato

Farnesil pirofostato

Escualeno

Colesterol Proteínas

isopreniladas

DolicolesProetínas

farnesiladas

HMG-CoA reductasa

Geranilgeranil pirofosfato

LipofílicasFluvastatinaSimvastatinaAtorvastatinaPitavastatina

RosuvastatinaPravastatina

Proteínas Geranilgeraniladas

Hidrofílicas


ESTATINAS

Rho

ROCKRhotekinCitron quinasa

mDIA MLC fosfatasa

Protein-kinase N-related quinasa

Rigidez aórticaPressión sanguínea

IRS-1

Insulin/PI3K/Akt

Hipertrofia cardíacaHipertensiónAngiogénesis

PKB/Akt FOXO

Supervivencia celular

Citoesqueleto de actina(Contracción CML)

Hipertensión pulmonar

Rac1

IRS: sustrato receptor de la insulina

Quinasa activada p21

Proteínas involucradas en el remodelado

del citoesqueleto

Proteinas activadoras de la GTPasa unida a

calmodulina

Proteínas síndrome Wiskott-

Aldrich Producción superóxido

P67 phox

↑NADPH oxidasa

ROS

Acetil CoA

HMG-CoA

Mevalonato

Farnesil pirofostato

Escualeno

Colesterol Proteínas

isopreniladas

DolicolesProetínas

farnesiladas

HMG-CoA reductasa

Geranilgeranil pirofosfato

LipofílicasFluvastatinaSimvastatinaAtorvastatinaPitavastatina

RosuvastatinaPravastatina

Proteínas Geranilgeraniladas

Hidrofílicas


STATINS HAVE BENEFICIAL EFFECTS IN ADDITION TO AND BEYOND BLOOD LIPID-

LOWERING


Documents

Effects of statins beyond hepatic cholesterol synthesis regulation