Dr. Marten-Steffens  Head of group CV  Members of the group

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Dr. Sabine Steffens
Lab. Biologie cardiovasculaire
HUG/Spécialités de Médecine
La Tulipe, Avenue Roseraie 64
1211 Genève 4

sabine.steffens@unige.ch

Tel.: 022 382 72 33
Fax: 022 382 72 45




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Pages updated the 17.11.2015
Reseach's subject | Group's publications | Research's domains

Role of the endocannabinoid system in atherosclerosis

Atherosclerosis is an inflammatory disease characterized by arterial lesions containing cholesterol, immune infiltrates, and connective-tissue elements. It is responsible for the major mortality causes, i.e. ischemic heart disease and cerebrovascular disease. Atherosclerotic lesions are pathological changes within the arterial wall which may lead to partial obstruction of the vascular lumen (stenosis). Various risk factors contribute to the initiation and progression of atherosclerosis, and increasing evidence supports a crucial role for inflammatory responses in this process.

Vascular smooth muscle proliferation and migration are pivotal events in the pathogenesis of atherosclerosis and are directly implicated in the failure of clinical interventions used to treat patients with coronary heart disease. For example, percutaneous transluminal angioplasty is an invasive procedure aimed to repair a stenotic blood vessel by inflating a balloon-tipped catheter at the site of the vascular narrowing followed by an insertion of an expandable wire mesh or hollow perforated tube (stent) into the reconstructed/dilated blood vessel to protect against re-narrowing. It often fails with the time because of the development of restenosis.

A growing body of evidence suggests that endocannabinoid signaling plays a critical role in the pathogenesis of atherogenesis and its clinical manifestations. The endocannabinoid system is composed of the two known receptors CB1 and CB2, their endogenous ligands (called endocannabinoids) and enzymes for ligand biosynthesis and inactivation. Rimonabant is the first CB1 antagonist being studied and approved as antiobesity drug in Europe and under review in the United States. Large randomized trials with rimonabant have demonstrated efficacy in treatment of overweight. In addition, multiple other cardiometabolic parameters were improved in the treatment groups, including increased levels of high density lipoprotein cholesterol and reduced triglycerides as well as improved glycemic control in prediabetes patients and in type 2 diabetic patients. Apart from CB1 receptors, CB2 receptors may also play a prominent role in atherosclerosis. Using an experimental mouse model of atherosclerosis, we have recently demonstrated that oral administration of low dose delta-9-Tetrahydrocannabinol (THC) inhibited plaque development, an effect that could be reversed by the CB2 antagonist SR144528.

The aim of our research studies is to study the precise role of the endocannabinoid system in the pathogenesis of atherosclerosis, restenosis and myocardial infarction and to test a potential therapeutic benefit of pharmacological intervention. To investigate this, we use both genetic (using receptor-deficient mice) as well as pharmacological (using receptor ligands and antagonists) approaches.

Our studies should help to better understand the complex cardiovascular effects of endocannabinoids and clarify their implication in atherosclerosis and its complications. A better knowledge of the endocannabinoid system may help to identify new targets for therapeutic intervention in cardiovascular disease and its complications such as restenosis and myocardial infarction. Our latest findings strongly support this hypothesis and provide the rationale for further investigations.




Group's publications

Cannabinoid receptor CB2 protects against balloon-induced neointima formation.
AMERICAN JOURNAL OF PHYSIOLOGY. HEART AND CIRCULATORY PHYSIOLOGY
2012 vol. 302(5) pp. 1064-1074
MOLICA F, MATTER CM, BURGER F, PELLI G, ZIMMER A, PACHER P, STEFFENS S

The activation of the cannabinoid receptor type 2 reduces neutrophilic protease-mediated vulnerability in atherosclerotic plaques.
EUROPEAN HEART JOURNAL
2012 vol. 33(7) pp. 846-856
MONTECUCCO F. AND AL.

Targeting the endocannabinod system to limit myocardial and cerebral ischemic and reperfusion injury.
CURRENT PHARMACEUTICAL BIOTECHNOLOGY
2011 vol. 13(1) pp. 46-58
TUMA R, STEFFENS S

Elevated endocannabinoid plasma levels are associated with coronary circulatory dysfunction in obesity.
EUROPEAN HEART JOURNAL
2011 vol. 32(11) pp. 1369-1378
QUERCIOLI A. AND AL

Role of CCL-2, CCR-2 and CCR-4 in cerulein-induced acute pancreatitis and pancreatitis-associated lung injury.
JOURNAL OF CLINICAL PATHOLOGY
2011 vol. 64(5) pp. 387-393
FROSSARD JL, LENGLET S, MONTECUCCO F, STEFFENS S, GALAN K, PELLI G, SPAHR L, MACH F, HADENGUE A

Mass spectrometry for the evaluation of cardiovascular diseases based on proteomics and lipidomics.
THROMBOSIS AND HAEMOSTASIS
2011 vol. 106(1) pp. 20-33
THOMAS A, LENGLET S, MACH F, DEGLON J, MANGIN P, CHAURAND P, WOLFENDER JL, STEFFENS S, STAUB C

High-throughput phospholipidic fingerprinting by online desorption of dried spots and quadrupole-linear ion trap mass spectrometry: evaluation of atherosclerosis biomarkers in mouse plasma.
ANALYTICAL CHEMISTRY
2010 vol. 82(15) pp. 6687-6694
THOMAS A, DEGLON J, LENGLET S, MACH F, MANGIN P, WOLFENDER JL, STEFFENS S, STAUB C

Chemokine CCL5/RANTES inhibition reduces myocardial reperfusion injury in atherosclerotic mice.
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
2010 vol. 48(4) pp. 789-798
BRAUNERSREUTHER V, PELLIEUX C, PELLI G, BURGER F, STEFFENS S, MONTESSUIT C, WEBER C, PROUDFOOT A, MACH F, ARNAUD CLAIRE

Systemic and intraplaque mediators of inflammation are increased in patients symptomatic for ischemic stroke.
STROKE
2010 vol. 41(7) pp. 1394-1404
MONTECUCCO F. AND AL.

Regulation and possible role of endocannabinoids and related mediators in hypercholesterolemic mice with atherosclerosis.
ATHEROSCLEROSIS.
2009 vol. 205(2) pp. 433-441
MONTECUCCO F, MATIAS I, LENGLET S, PETROSINO S, BURGER F, PELLI G, BRAUNERSREUTHER V, MACH F, STEFFENS S, DI MARZO V

CB(2) cannabinoid receptor activation is cardioprotective in a mouse model of ischemia/reperfusion.
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
2009 vol. 46(5) pp. 612-620
MONTECUCCO F, LENGLET S, BRAUNERSREUTHER V, BURGER F, PELLI G, BERTOLOTTO M, MACH F, STEFFENS S

Effect of blockage of the endocannabinoid system by CB(1) antagonism on cardiovascular risk.
PHARMACOLOGICAL REPORTS
2009 vol. 61(1) pp. 13-21
MACH F, MONTECUCCO F, STEFFENS S

Statins inhibit C-reactive protein-induced chemokine secretion, ICAM-1 upregulation and chemotaxis in adherent human monocytes.
RHEUMATOLOGY : OFFICIAL JOURNAL OF THE BRITISH SOCIETY FOR RHEUMATOLOGY
2009 vol. 48(3) pp. 233-242
MONTECUCCO F, BURGER F, PELLI G, POKU NK, PERLIER C, STEFFENS S, MACH F

The emerging role of the endocannabinoid system in cardiovascular disease.
SEMINARS IN IMMUNOPATHOLOGY
2009 vol. 31(1) pp. 63-77
PACHER P, STEFFENS S

The inflammatory response as a target to reduce myocardial ischaemia and reperfusion injury.
THROMBOSIS AND HAEMOSTASIS
2009 vol. 102(2) pp. 240-247
STEFFENS S, MONTECUCCO F, MACH F

CB2 cannabinoid receptor agonist JWH-015 modulates human monocyte migration through defined intracellular signaling pathways.Am J Physiol Heart Circ Physiol
AMERICAN JOURNAL OF PHYSIOLOGY. HEART AND CIRCULATORY PHYSIOLOGY
2008 vol. 294(3) pp. 1145-1155
MONTECUCCO F, BURGER F, MACH F, STEFFENS S

A novel RANTES antagonist prevents progression of established atherosclerotic lesions in mice.
ARTERIOSCLEROSIS, THROMBOSIS AND VASCULAR BIOLOGY
2008 vol. 28(6) pp. 1090-1096
BRAUNERSREUTHER V, STEFFENS S, ARNAUD C, PELLI G, BURGER F, PROUDFOOT A, MACH F

Cannabinoid receptors in acute and chronic complications of atherosclerosis.
BRITISH JOURNAL OF PHARMACOLOGY
2008 vol. 153(2) pp. 290-298
MACH F, MONTECUCCO F, STEFFENS S

Tumor necrosis factor-alpha (TNF-alpha) induces integrin CD11b/CD18 (Mac-1) up-regulation and migration to the CC chemokine CCL3 (MIP-1alpha) on human neutrophils through defined signalling pathways.
CELLULAR SIGNALLING
2008 vol. 20(3) pp. 557-568
MONTECUCCO F, STEFFENS S, BURGER F, DA COSTA A, BIANCHI G, BERTOLOTTO M, MACH F, DALLEGRI F, OTTONELLO L

Adiponectin and adaptive immunity: linking the bridge from obesity to atherogenesis.
CIRCULATION RESEARCH
2008 vol. 102(2) pp. 140-142
STEFFENS S, MACH F

C-reactive protein (CRP) induces chemokine secretion via CD11b/ICAM-1 interaction in human adherent monocytes.
JOURNAL OF LEUKOCYTE BIOLOGY
2008 vol. 84(4) pp. 1109-1119
MONTECUCCO F, STEFFENS S, BURGER F, PELLI G, MONACO C, MACH F

The role of the endocannabinoid system in atherosclerosis.
JOURNAL OF NEUROENDOCRINOLOGY
2008 vol. 20 pp. 53-57
MACH F, STEFFENS S

Insulin resistance: a proinflammatory state mediated by lipid-induced signaling dysfunction and involved in atherosclerotic plaque instability.
MEDIATORS OF INFLAMMATION
2008 vol. 2008 pp. 767623-767623
MONTECUCCO F, STEFFENS S, MACH F

Ccr5 but not Ccr1 deficiency reduces development of diet-induced atherosclerosis in mice
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
2007 vol. 27 pp. 373-379
BRAUNERSREUTHER V, ZERNECKE A, ARNAUD C, LIEHN EA, STEFFENS S, SHAGDARSUREN E, BIDZHEKOV K, BURGER F, PELLI G, LUCKOW B, MACH F, WEBER C

The immune response is involved in atherosclerotic plaque calcification: could the RANKL/RANK/OPG system be a marker of plaque instability?
CLINICAL & DEVELOPMENTAL IMMUNOLOGY
2007 vol. 2007 pp. 75805-
MONTECUCCO F, STEFFENS S, MACH F

The specific role of chemokines in atherosclerosis
THROMBOSIS AND HAEMOSTASIS
2007 vol. 97 pp. 714-721
BRAUNERSREUTHER V, MACH F, STEFFENS S

Simvastatin modulates chemokine and chemokine receptor expression by geranylgeranyl isoprenoid pathway in human endothelial cells and macrophages
ATHEROSCLEROSIS
2006 vol. 188 pp. 51-58
VEILLARD NR, BRAUNERSREUTHER V, ARNAUD C, BURGER F, PELLI G, STEFFENS S, MACH F

Short-term treatment with anti-CD3 antibody reduces the development and progression of atherosclerosis in mice
CIRCULATION
2006 vol. 114 pp. 1977-1984
STEFFENS S, BURGER F, PELLI G, DEAN Y, ELSON G, KOSCO-VILBOIS M, CHATENOUD L, MACH F

Cannabinoid receptors in atherosclerosis
CURRENT OPINION IN LIPIDOLOGY
2006 vol. 17(5) pp. 519-526
STEFFENS S, MACH F

Drug insight: Immunomodulatory effects of statins--potential benefits for renal patients?
NATURE CLINICAL PRACTICE NEPHROLOGY
2006 vol. 2(7) pp. 378-387
STEFFENS S, MACH F

Statins reduce interleukin-6-induced C-reactive protein in human hepatocytes: new evidence for direct antiinflammatory effects of statins.
ARTERIOSCLEROSIS, THROMBOSIS AND VASCULAR BIOLOGY
2005 vol. 25(6) pp. 1231-1236
ARNAUD CLAIRE, BURGER FABIENNE, STEFFENS S, VEILLARD NIELS, NGUYEN TUAN HUY, MACH FRANCOIS

Differential influence of chemokine receptors CCR2 and CXCR3 in development of atherosclerosis in vivo.
CIRCULATION
2005 vol. 112(6) pp. 870-878
VEILLARD NIELS, STEFFENS S, PELLI G, LU B, KWAK BR, GERARD C, CHARO IF, MACH F

Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice.
NATURE
2005 vol. 434(7034) pp. 782-786
STEFFENS S, VEILLARD N, ARNAUD C, PELLI G, BURGER F, STAUB C, KARSAK M, ZIMMER A, FROSSARD JL, MACH F

Mechanisms of thymidine kinase/ganciclovir and cytosine deaminase/ 5-fluorocytosine suicide gene therapy-induced cell death in glioma cells.
ONCOGENE : AN INTERNATIONAL JOURNAL
2005 vol. 24(7) pp. 1231-1243
FISCHER U, STEFFENS S, FRANK S, RAINOV NG, SCHULZE-OSTHOFF K, KRAMM CM

Differential expression patterns of proinflammatory and antiinflammatory mediators during atherogenesis in mice
ARTERIOSCLEROSIS, THROMBOSIS AND VASCULAR BIOLOGY
2004 vol. 24(12) pp. 2339-2344
VEILLARD NR, STEFFENS S, BURGER F, PELLI G, MACH F

Inflammation and Atherosclerosis.
HERZ
2004 vol. 29 (8) pp. 741-748
STEFFENS S, MACH F

Transduction of human glial and neuronal tumor cells with different lentivirus vector pseudotypes
JOURNAL OF NEURO-ONCOLOGY
2004 vol. 70(3) pp. 281-288
STEFFENS S, TEBBETS J, KRAMM CM, LINDEMANN D, FLAKE A, SENA-ESTEVES M

Optimized large-scale production of high titer lentivirus vector pseudotypes
JOURNAL OF VIROLOGICAL METHODS
2004 vol. 122(2) pp. 131-139
SENA-ESTEVES M, TEBBETS JC, STEFFENS S, CROMBLEHOLME T, FLAKE AW

A neuroblastoma-selective suicide gene therapy approach using the tyrosine hydroxylase promoter
PEDIATRIC RESEARCH : AN INTERNATIONAL JOURNAL OF CLINICAL, LABORATORY AND DEVELOPMENTAL INVESTIGATION
2004 vol. 56(2) pp. 268-277
STEFFENS S, SANDQUIST A, FRANK S, FISCHER U, LEX C, RAINOV NG, KRAMM CM


Research's domains