effects of statins beyond hepatic cholesterol synthesis regulation
DESCRIPTION
La Prof.ª Lina Badimon, vicepresidenta de la Sociedad Española de Cardiología (SEC), participa en la sesión 'Qué hay de nuevo respecto al papel de las estatinas. Control lipídico en los pacientes de alto riesgo CV en España', perteneciente a la 'Jornada Galáctica sobre Guías de Lípidos y objetivos a alcanzar en los pacientes de más alto riesgo cardiovascular' (Málaga, 4-5 abril, 2014). Accede a la jornada completa en http://guiaslipidos.secardiologia.esTRANSCRIPT
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
Cholesterol and Lipoproteinsin CoronaryArteryDisease
Bloodcholesterol pool•Vesselwalllipid pool•Cellulareffects
Intestinal CholesterolAbsorption
HepaticCholesterolSynthesis
HYPERCHOLESTEROLEMIA ATHEROSCLEROSIS
Badimon L. 2014
Cholesterol and Lipoproteinsin CoronaryArteryDisease
Bloodcholesterol pool•Vesselwalllipid pool•Cellulareffects
Intestinal CholesterolAbsorption
HepaticCholesterolSynthesistreatment
Badimon L. 2014
Cholesterol and Lipoproteinsin CoronaryArteryDisease
Bloodcholesterol pool•Vesselwalllipid pool•Cellulareffects
Intestinal CholesterolAbsorption
HepaticCholesterolSynthesistreatment
Badimon L. 2014
Cholesterol and Lipoproteinsin CoronaryArteryDisease
bloodcholesterol pool•Vesselwalllipid pool•Cellulareffects
Intestinal CholesterolAbsorption
HepaticCholesterolSynthesistreatment
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
ICCC-Badimon L. 2014
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
ICCC-Badimon L. 2014
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
ICCC-Badimon L. 2014
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
ICCC-Badimon L. 2014
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
ICCC-Badimon L. 2014
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
ICCC-Badimon L. 2014
Sardella G, Catheter CardiovascInterv. 2012
ROMA TRIAL: ROSUVASTATIN PRETREATMENT IN ELECTIVE PCI
Statin-naif pts/40mg rosu/24h pre-PCI
P>0.001
ICCC-Badimon L. 2014
Norris DM, Cardiol Rev 2012 Nov 20(6) 319-24
StatinLoadingBeforePercutaneousCoronaryInterventionto Reduce PeriproceduralMyocardialInfarction
ICCC-Badimon L. 2014
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
ICCC-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
ICCC-Badimon L. 2014
STATINS HAVE BENEFICIAL EFFECTS IN ADDITION TO AND BEYOND BLOOD LIPID-
LOWERING
ICCC-Badimon L. 2014