les récepteurs de l’inflammation: l’exemple des eicosanoïdes
TRANSCRIPT
Magnus Bäck M.D., Ph.D.
Center for Molecular Medicine, Karolinska Institutet
Department of Cardiology, Karolinska University Hospital
Stockholm – Sweden
Les récepteurs de l’inflammation: l’exemple des eicosanoïdes
Conflicts of Interest: None
LXA4
ARACHIDONIC ACID
COX I & II
FLAP
5-LO
LTA4
PGD2 PGE2 PGF2a PGI2 TXA2 LTB4 LTC4
Isoprostanes
p450 EETs
15-LO
Cardiovascular Eicosanoid Research
Bäck et al., Pharmacol Rev 2011;63:539
Eicosanoid Receptors: BLT1R
Bäck et al., Pharmacol Rev 2011;63:539
BLT1
BLT2
CysLT1
CysLT2
Cardiovascular Eicosanoid Research
Montelukast SINGULAIR®
Zafirlukast ACCOLATE® Pranlukast ONON®
Endothelial Cells Leukocyte adhesion Release of vasoactive mediators
Leukocytes Monocyte recruitment and activation
Cytokine and protease secretion
T-lymphocyte-driven inflammation
PMN chemotaxis and protease release
Vascular SMCs
Migration, Proliferation
Vasoconstriction
MK-886
Vehicle
Bäck et al., Circ Res 2007; 100:946
MK-886 decreased
atherosclerosis
in ApoE-/- Mice
BIIL284 decreased
intimal hyperplasia after
vascular injury in rats
BIIL284
Vehicle
Bäck et al., PNAS 2005;102:17501
BIIL 284 decreased in-
stent stenosis in
hyperlipidemic rabbits
BIIL284
Vehicle
Hlawaty et al., ATVB 2009;29:518
Human Carotid Atherosclerotic Lesions
Eaton et al. J Mol Med 2012;90:1223
Merge aSM-actin CysLT1R
Human Coronary Artery Smooth Muscle Cells
Merge aSM-actin CysLT1R
Contr BAPTA-AM EGTA
* * PA
I-2 m
RNA leve
ls
(2-D
DC
T)
0
6
5
4
3
2
1
*
LTC4 +MK571
PAI-2 m
RNA leve
ls
(Fol
d c
han
ge)
0
8
6
4
2
Contr LTC4
Eaton et al. J Mol Med 2012;90:1223
LTC4
+LPS CysL
T1R m
RNA L
eve
ls
(fol
d c
han
ge)
* *
Aortic Valve Stenosis
Leukotriènes
Stress mécanique
Cellules endothéliales
LDL
Lymphocyte T
Monocyte/ Macrophage
Cellule interstitielle valvulaire
Ostéoclaste
RECRUTEMENT & ACTIVATION LEUCOCYTAIRE
REMODELAGE VALVULAIRE
OSSIFICATION HÉTÉROTOPIQUE MMPs
Ostéopontine
TGFb APOPTOSE
Ostéoblaste
RUNx2
RUNx2 [Ca2+]↑
Ostéocalcine
BMPs
MMPs
DEPÔT CALCAIRE
CathépsineS
RANK
RANKL
OPG
CysLT1
DRO TRANSDIFFÉRENCIATION PHÉNOTYPIQUE
m ↓
Sain
Epaissi Calcifié
Bäck M, AMC Pratique 2012, 211:23
Nagy et al. Circulation. 2011;123:1316
Vimentin CysLT1 Receptor
Merge
Valvular Interstitial Cells treated with LTC4
LTC4
Control
LTC4
Control
30 min 24 h 2 weeks
BMP-2
mR
NA
Expr
ess
ion
(2
-DD
CT)
mR
NA
Expr
ess
ion
(2-Δ
ΔC
T)
PARP-1
*
*
Nagy et al. Circulation. 2011;123:1316 Nagy et al. BBRC. 2012;420:671
Summary
Leukotriene receptors transduce cardiovascular inflammation through effects on leukocytes, and on structural cells of the vascular wall and cardiac valves.
LT synthesizing enzymes and receptors are expressed in atherosclerotic lesions and stenotic aortic valves.
Leukotriene C4 induces nuclear calcium signaling and alterations of gene expression in vascular smooth muscle cells and valvular interstitial cells.
Anti-leukotrienes reduce atherosclerosis and intimal hyperplasia after vascular injury in animal models.
Leukotriene Receptors
Clinical Applications
Leukotriene Receptor Antagonists as First-Line or Add-on Asthma-Controller Therapy
Price et al., New Engl J Med 2011;364:1695
First-Line Controller Therapy Trial
PEF
(%
of
pred
icte
d)
Add-on Therapy Trial
Inhaled corticosteroids
Leukotriene Rec Antagonists
Long Acting b-agonists
Leukotriene Rec Antagonists
hs-CRP
Leukotriene Receptor Antagonists Decrease Inflammation in Asthmatics
Retrospective analysis of a RCT comparing placebo with Montelukast (10 mg/d).
Allayee et al., Chest 2007;132:868
The Register on Prescribed and Dispensed Pharmaceuticals in Sweden The Hospital Discharge Register The Cause of Death register Registers at Statistics Sweden -Swedish Total Population Register -Educational Register -Income Register To define the study population and to address socioeconomic confounding as a cause of observed associations.
Epidemiological Registry Study
Leukotriene Receptor Antagonists and Cardiovascular Outcome
All Swedish residents >18 years
Subjects with prior myocardial
infarction N=153,937
Subjects with prior ischemic
stroke N=132,291
July 1, 2005
Dec 31, 2008
Myocardial Infarction (ICD-10: I21) Ischemic Stroke (ICD-10: I63)
Subjects without prior myocardial infarction
N=6,910,923
Subjects without prior
ischemic stroke
N=6,932,578
Sex Age Education: low /mid Income : low / mid Respiratory diagnosis: COPD, Asthma Respiratory medication prescription: Inhaled corticosteroids, Inhaled adrenergics, Inhaled anticholinergics, Sodium cromoglycate, Teophylamine Cardiovascular medication prescription: Betablockers (ATC C07), Calcium channel blockers (ATC C08), ACE-inhibitors & Angiotensin receptor blockers (ATC C09), Lipid modifying agents (ATC C10), Antithrombotic agents (Aspirin, clopidogrel)
Adjustments
Leukotriene Receptor Antagonists and Cardiovascular Outcome
No. of
events
Event rate
(per 1000 PYAR) HR (95% CI) P-value
Incident Events 61,723 2.54 (2.52-2.56) 0.95 (0.80-1.1) 0.54
Recurrent Events 13,596 36.6 (36.0-37.2) 0.62 (0.39-1.0) 0.05
ACE-inh/ARB users 0.97 (0.55-1.72)
ACE-inh/ARB non-users 0.34 (0.14-0.82)
Ischemic Stroke
Ingelsson, Yin & Bäck. JACI 2012;129:702
No ACE inh/ARB 0.34 (0.14-0.82)
ACE inh/ARB 0.97 (0.55-1.72)
No. of
events
Event rate
(per 1000 PYAR) HR (95% CI) P-value
Incident Events 78,843 3.26 (3.24-3.28) 0.97 (0.85-1.1) 0.58
Recurrent Events 18,620 40.7 (40.1-41.3) 0.93 (0.71-1.2) 0.58
Myocardial Infarction
Females 6,844 46.3 (45.2-47.4) 1.25 (0.89-1.8) 0.19
Males 11,776 38.8 (38.2-39.6) 0.65 (0.43-0.99) 0.046
Ingelsson, Yin & Bäck. JACI 2012;129:702
Montelukast use was associated with border-line significant beneficial effects in the secondary prevention of ischemic stroke. Significant interaction with angiotensin-modifying drugs. Montelukast use was associated with a significantly lower risk for recurrent myocardial infarction in males, but not in females. These data provide a first indication for a potential role of leukotriene receptor antagonists in secondary prevention of cardiovascular disease.
Leukotriene Receptor Antagonists and Cardiovascular Outcome
Ingelsson, Yin & Bäck. JACI 2012;129:702
Bäck et al. Br J Clin Pharmacol. 2013;75:280
Acknowledgements Cardiovascular Eicosanoid Research
Edit Nagy Alison Eaton Daniel C. Andersson Sangeetha Ashok Kumar Marcelo Petri Center for Molecular Medicine Göran K. Hansson Department of Cardiology Reidar Winter Department of Medical Epidemiology & Biostatistics Erik Ingelsson Li Yin
Bichat Hospital, Paris Jean-Baptiste Michel
Charles Brink Xavier Houard Hania Hlawaty
INSERM, Montpellier Hospital
Jérémy Fauconnier Ariane Sultan
INSERM, Grenoble Hospital
Françoise Stanke-Labesque
INSERM, Nancy Hospital Athanase Benetos
Carlos Labat
French-Swedish Collaborations