Main aim of NORVAS is to identify non-coding RNA based therapies and biomarkers that enable us to combat the burden of vascular diseases in general, and abdominal aortic aneurysms and carotid artery stenosis and subsequent stroke in particular. Abdominal aortic aneurysms (AAAs) are defined as a permanent dilation of the abdominal aorta that predisposes to the fatal consequence of rupture. The diagnosis of a AAA is commonly an accidental finding, although there is an increasing number of screening programs targeting high-risk populations. A number of screens demonstrate that the disease prevalence is approximately 5% in men and 1 % in women over 60 years of age. Sixty percent of patients with AAAs die of other cardiovascular causes, such as stroke or myocardial infarction, suggesting a relationship between AAAs and atherosclerosis. Currently, the only available treatment option remains surgical repair or endovascular stenting. Besides being not feasible to treat the early stages of the disease, both interventional procedures do carry a potential operative risk, and thus appear only effective in preventing aortic rupture. With a mortality rate of 30%, stroke is the fourth leading cause of death and also the leading cause of adult disability in Western countries, with ischemic stroke accounting for approximately 85% of all cases. Vulnerable atherosclerotic plaques in the common carotid arteries are considered the most dominant initiator for ischemic forms of stroke (approx. 85% of all strokes). Some of the mechanisms proposed to contribute to unstable carotid atheroma development are identical to the ones being involved in AAA development and rupture, including apoptosis and insufficient proliferation of smooth muscle cells within the fibrous cap of advanced atherosclerotic carotid lesions. Again, the most common form of treatment in patients with an ischemic stroke is surgical removal of the affected carotid artery plaque. Thus, here all novel forms of treatments that can stabilise late stage and rupture prone carotid artery plaques are highly desirable. The key contribution of non-coding RNAs in regulating gene expression has recently received great attention. Using transcriptomic profiling technology on unique diseased human biobank material, we have identified several microRNAs (e.g. miR-21, miR-210) and long non-coding RNAs (H19, MIAT, NUDT6, SLFNL-AS1) as novel key regulators of smooth muscle cell survival in the vascular system. We performed studies in disease-relevant experimental in vivo models (rodents and LDLR-/- Yucatan mini-pigs) and developed novel in vitro models (aorta-on-a-chip) to functionally assess how inhibition of these non-coding RNAs influence aortic aneurysm progression and atherosclerotic plaque vulnerability. To enhance the translational feasibility of our findings, we will continue to utilise clinically established delivery tools, such as drug eluting stents and balloons, to locally administer our ncRNA modulators of interest to the vascular system. Furthermore, we screened longitudinal cohort studies that follow-up on individuals at different stages of aortic aneurysm disease, enabling us to investigate the prospective biomarker potential of ncRNAs in recognizing aneurysm growth patterns and patient’s acute and future risk of aortic rupture.
