COL5A1 Variants Cause Aortic Dissection by Activating TGF-β-Signaling Pathway

Background Aortic dissection (AD) is one of the most life-threatening cardiovascular diseases that exhibit high genetic heterogeneity. However, it is unclear whether variants within the COL5A1 gene can cause AD. Therefore, we intend to determine whether COL5A1 is a causative gene of AD. Methods and Results We performed targeted sequencing in 702 patients with unrelated sporadic AD and 163 matched healthy controls using a predesigned panel with 152 vessel matrix-related genes. As a result, we identified that 11 variants in COL5A1 caused AD in 11 out of the 702 patients with AD. Furthermore, Col5a1 knockout (Col5a1) rats were generated through the CRISPR/Cas9 system. Although there was no spontaneous AD, electron microscopy revealed a fracture of elastic fibers and disarray of collagenous fibers in 6-week-old Col5a1 rats, but not in WT rats (93.3% versus 0.0%, P<0.001). Three-week-old rats were used to induce the AD phenotype with β-aminopropionitrile monofumarate for 4 weeks followed by angiotensin II for 72 hours. The β-aminopropionitrile monofumarate and angiotensin II-treated rat model confirmed that Col5a1 rats had considerably higher AD incidence than WT rats. Subsequent mechanism analyses demonstrated that the transforming growth factor-β-signaling pathway was significantly activated in Col5a1 rats. Conclusions Our findings, for the first time, revealed a relationship between variants in COL5A1 and AD via targeted sequencing in 1.57% patients with sporadic aortic dissection. The Col5a1 knockout rats exhibited AD after an intervention, indicating that COL5A1 is a causative gene of AD. Activation of the transforming growth factor-β-signaling pathway may be implicated in the pathogenesis of this kind of AD.