Research Programme
Sabine´s research is focused on the role of the endocannabinoid system and other endogenous signalling pathways during inflammatory processes underlying atherosclerosis and cardiac repair. The endocannabinoid system has recently evolved as an endogenous lipid signaling system that is activated in a multitude of disorders, including atherosclerosis. However, the pathophysiological effect of elevated endocannabinoid tone in cardiovascular disease is not well understood. We therefore aim to clarify the precise pathophysiological relevance of cannabinoid receptors and other endogenous signalling pathways in cardiovascular disease, with particular focus on the hematopoietic stem cell niche, innate immune functions and cholesterol metabolism.
During the post-myocardial infarction inflammation resolution phase, pro-inflammatory macrophages are thought to undergo local conversion to resolution–mediating macrophages. Hence, reprogramming macrophages in the heart to a reparative state seems to be an attractive therapeutic strategy to improve infarct repair. In ongoing studies, we are investigating signalling pathways and local regulators of the cardiac microenvironment promoting resolution of post-myocardial infarction inflammation and macrophage differentiation into a reparative phenotype. In this context, we recently identified neutrophils as pivotal modulators of the healing response after myocardial infarction and consequently cardiac repair. Furthermore, we are interested in understanding how the circadian rhythm affects myocardial infarction outcome and underlying inflammatory responses. Circadian rhythms are biological processes displaying endogenous oscillations of about 24-h and are known to play crucial role in physiology.
Role of endocannabinoids in atherosclerosis
Endocannabinoids are endogenous lipid mediators involved in cardiometabolic disorders, which activate CB1 and CB2 cannabinoid receptors in the brain, peripheral tissues and immune cells. Unstable coronary artery disease patients have increased plasma levels of endocannabinoids, and it suggested that these mediators play a causal role in atherosclerosis. Clinical studies with cannabinoid receptor CB1 antagonist rimonabant as anti-obesity drug revealed reduced cardiovascular risk factors, including changes in plasma lipid profiles and CRP levels. However, rimonabant was withdrawn from the market because of too severe CNS side effects. Selective drugs targeting peripheral CB1 receptors are therefore under development, and it remains to be investigated whether inhibition of peripheral CB1 signaling is as efficient in improving cardiovascular risk factors.
Endocannabinoid signalling also plays a role in acute complications of atherosclerosis such as myocardial infarction. Necrosis of the infarcted myocardium triggers a healing response in order to remove and replace necrotic tissue. Neutrophils are among the first immune cells infiltrating the infarct area. Despite their well-established detrimental role in contributing to ischemia-reperfusion, they are also required for a coordinated healing response by promoting the transition from the inflammatory to the resolution phase. However, there is a critical balance between immune cell counts recruited to the myocardium and quality of infarct healing, which is crucially affected by circadian rhythms.
Further reading:
Montecucco F et al. (2012). The activation of the cannabinoid receptor type 2 reduces neutrophilic protease-mediated vulnerability in atherosclerotic plaques. Eur Heart J 2011; 33: 846-856
Steffens, S., and Pacher, P. (2015). The Activated Endocannabinoid System in Atherosclerosis: Driving Force or Protective Mechanism? Current Drug Targets 2015; 16: 334-41.
Horckmans M et al. Neutrophils orchestrate post-myocardial infarction healing by polarizing macrophages towards a reparative phenotype Eur Heart J 2017; 38:187-197
Schloss MJ et al.. The time-of-day of myocardial infarction onset affects healing through oscillations in cardiac neutrophil recruitment. EMBO Molecular Medicine, 2016, 8:937-48
Soehnlein et al. Neutrophils as protagonists and targets in chronic inflammation. Nat Rev Immunol (March 13, 2017 advance online)
Our mission: To reduce the burden of cardiovascular disease.