The Athero-Resilience Project: Systems Approaches for the Discovery of Atheroprotective Targets

From Risk to Protection: The Two Sides of a Coin
Age-dependent Intimal Thickenig
Brief Review

Resilience to Atherosclerosis

Atherosclerosis (ASS) is the leading cause of myocardial infarction, stroke and premature death. While the molecular and cellular mechanisms of ASS are incompletely understood, research has successfully focused on lipids, blood pressure, diabetes and inflammation as major causes of vascular injury and plaque formation. Indeed, lowering of blood pressure, low density lipoprotein, cholesterol (LDL-C), smoking cessation and novel anti-diabetic drugs and even anti-inflammatory approaches have been shown to reduce major adverse cardiovascular events (MACE). However, in spite of all this, there is a substantial remaining cardiovascular (CV) risk with up to 20% of patients experiencing myocardial infarction, stroke or death in the first year after an acute coronary syndrome (ACS). Notably, although CV risk factors closely relate to ASCVD and mortality there is a huge spread of individual data. Even in familial hypercholesteremia, some never develop an ACS or die of ASCVD. This obvious epidemiological observation has hardly been considered as research focused only on vascular injury as the sole cause of ASCVD.

With this project, we aim to decipher the protective factors of the IMA providing resilience to ASS using a multiomics approach. We have sequenced the RNA profile of the IMA, coronary and radial artery and saphenous veins and aim to understand, using bioinformatics, differentially expressed and activated pathways of these blood vessels prone or not to ASS. We will now confirm these results at the protein level using proteomics and eventually confirming the biological activity of candidate proteins in endothelial and vascular smooth muscle cells of these arteries in culture. To that end, we brought 3 centres with complimentary expertise together. In Zurich, the Center for Molecular Cardiology has long-standing experience in the vascular biology of the IMA, coronary artery and saphenous vein working with CV Surgery and Molecular Pathology and the functional genomic centre. Geneva has specific expertise in single cell multiomics of endothelial and vascular smooth muscle cells at different anatomical locations. Finally, the King’s College proteomic service in London, UK, will perform extensive proteomic studies of these tissues.

The extensive complimentary and inter-disciplinary expertise of the involved centres will provide a knowledge platform, address the question on what protective factors are expressed in the IMA, but not in other arteries prone to ASCVD as a basis for novel therapeutic strategies in ASS to further reduce the remaining CV risk.

 

Participating Institutions

Synergia Collaborators

 

Possible Mechanisms of Athero-Resilience

Fueled by the global surge in aging, atherosclerotic cardiovascular disease reached pandemic dimensions putting affected individuals at enhanced risk of myocardial infarction, stroke, and premature death. Atherosclerosis is a systemic disease driven by a wide spectrum of factors, including cholesterol, pressure, and disturbed flow. Although all arterial beds encounter a similar atherogenic milieu, the development of atheromatous lesions occurs discontinuously across the vascular system. Indeed, the internal mammary artery possesses unique biological properties that confer protection to intimal growth and atherosclerotic plaque formation, thus making it a conduit of choice for coronary artery bypass grafting. Its endothelium abundantly expresses nitric oxide synthase and shows accentuated nitric oxide release, while its vascular smooth muscle cells exhibit reduced tissue factor expression, high tPA (tissue-type plasminogen activator) production and blunted migration and proliferation, which may collectively mitigate intimal thickening and ultimately the evolution of atheromatous plaques. We aim here to provide insights into the anatomy, physiology, cellular, and molecular aspects of the internal mammary artery thereby elucidating its remarkable resistance to atherogenesis. We propose a change in perspective from risk to resilience to decipher mechanisms of atheroresistance and eventually identification of novel therapeutic targets presently not addressed by currently available remedies.

Systemic Cardiovascular Risk Factors (eg, LDL-C)