Experimental evidences of conventional drugs efficacy in counteracting aortic fibrosis and new possible approaches for a better prognosis and a personalized management of Marfan patients

Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the FBN1 gene that in the aorta cause the formation of weak and disordered elastic fibers, leading to a weakened vascular wall, the early formation of thoracic aortic aneurysms (TAAs) and dissection (1). The role of fibrillin-1 is structural but also regulatory since it is also involved in the TGF-β1 binding, thus preventing its activity (2). Currently, pharmacological treatments include antihypertensive drugs aimed to delay TAA progression but, in the relatively short time, patients inevitably undergo surgery. Currently, aortic diameter larger than 5 cm is still the most used eligible criterion for surgery (3) but scientific evidences reported complications also at smaller aortic sizes, so other markers are needed to better identify high-risk MFS TAA patients (4). Previously, we documented that MFS TAA tissues and blood show a strong miR-632 up-regulation, induced by TGFb hyperactivation, compared to non-MFS TAA (5, 6). In addition, we found out that miR-632 deregulation is involved in the fibrotic process of MFS TAA (5).

We evaluated the possible beneficial effects of conventional therapies and miR-632 inhibitor in counteracting fibrosis and correlate miR-632 circulating levels with MFS clinical parameters.

Small fragments of aortic tunica media tissues, derived from non-MFS patients underwent surgery for aortic replacement, were stimulated with TGFb1 and treated with antihypertensive drugs (β-blocker, ACE inhibitor and sartan, alone or in combination) or transfected with miR-632 inhibitor for 24 hours. Serum samples derived from MFS patients, not yet eligible for surgery, were collected to evaluate miR-632 levels. Gene expression analysis were carried out in order to assess miR-632 and fibrosis markers. Elisa assays were performed on serum samples for measuring circulating general fibrosis markers.

We demonstrated that antihypertensive treatments, in particular sartan alone, significantly reduced miR-632 and fibrotic biomarker expression. The same was true for miR-632 inhibitor transfection that proven to be effective in counteracting fibrosis. Moreover, miR-632 circulating levels in MFS patients did not correlate with aortic root diameters, suggesting that instrumental parameters are not good indicators of aortic wall structural alterations, as previously reported. In fact, we demonstrated that higher circulating levels of miR-632 correlated with higher fibrosis markers.

Our findings demonstrated the local efficacy of conventional drugs, in particular sartan alone, in counteracting aortic wall fibrosis as well as the effectiveness of direct miR-632 inhibition. Therefore, we suggest miR-632 as a promising therapeutic target but also as a potential non-invasive specific prognostic factor of aortic wall state to better identify MFS patients with high-risk of cardiovascular complications.