Effects of statins beyond hepatic cholesterol synthesis regulation

Effects of statins beyond hepatic cholesterol
synthesis regulation:
Managing Cardiovascular Risk In the 21st Century
Lina Badimon
Barcelona CardiovascularScienceCenter (CSIC-ICCC)
Hospital de la Santa Creui Sant Pau
Málaga, April 2014

Cholesterol and Lipoproteins
in CoronaryArteryDisease
Bloodcholesterol pool
•Vesselwalllipid pool
•Cellulareffects
Intestinal CholesterolAbsorption
HepaticCholesterolSynthesis
Badimon L. 2014

•Cellulareffects
HYPERCHOLESTEROLEMIA ATHEROSCLEROSIS
Badimon L. 2014

•Cellulareffects
treatment
Badimon L. 2014

bloodcholesterol pool
•Cellulareffects
treatment
Badimon L. 2014

Changeincoronary
arterydiameter(%)
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
Episodesof
ischemia/48h
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)
%regeneratedarea
control
agLDL
agLDL
control
8h6h
12h6h
12h
0h

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
woundcoverage(%)
C
C+R
nLDL
nLDL+R
C
C+R
agLDL
agLDL+R
0
20
40
60
80
100
woundcoverage(%)
0 2 4 6 8 12
nLDL agLDL
hours hours
STATINS REVERT THE
PATHOLOGICAL EFFECTS
OF LDL IN THE VESSEL WALL
PadroT,LuganoR,GarciaM,BadimonL.PlosOne2012

PROTEOMIC INVESTIGATION ON STATIN EFFECTS ON HUMAN CORONARY VASCULAR CELLS
PadroT,LuganoR,GarciaM,BadimonL.PlosOne2012
MRLC

MolinsB, Peña E, PadroT, CasaniL, MendietaC, Badimon L. ATVB 2010
AHA- KARL LINK AWARD – BEST ARTICLE ON THROMBOSIS OF 2010
platelet surface GRP78 (red)
platelet membrane receptor GPIIIa (green).
Control
Resting
Platelets
Control
Sheared
(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
*
*
MPD(m2/field)
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
StatinLoadingBeforePercutaneousCoronaryIntervention
to 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
ROCKRhotekin
Citron quinasa
mDIA MLC fosfatasa
Protein-kinase N-related quinasa
Rigidez aórtica
Pressión 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
Dolicoles
Proetínas
farnesiladas
HMG-CoA
reductasa
Geranilgeranil
pirofosfato
Lipofílicas
Fluvastatina
Simvastatina
Atorvastatina
Pitavastatina
Rosuvastatina
Pravastatina
Proteínas
Geranilgeraniladas
Hidrofílicas

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

Effects of statins beyond hepatic cholesterol synthesis regulation

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