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.