Journal of the American Heart Association · 2026
TRPC1 Promotes Thoracic Aortic Dissection Through Inducing Proinflammatory Phenotype of Vascular Smooth Muscle Cells.
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Yang Liu, Li Qi, Pan Xujie, Yuan Menglu, Shi Yi, Zhang Enbo, Yu Fan, Feng Lei, Shao Jing, Liu Guizhu
Аннотация
BACKGROUND: Thoracic aortic dissection (TAD) is a life-threatening vascular disease that lacks effective pharmacological treatment. Canonical transient receptor potential (TRPC) channels are involved in regulating various cardiovascular functions, yet their roles in TAD have not been elucidated.
METHODS: Three-week-old male mice were administered β-aminopropionitrile dissolved in drinking water for 28 days to induce TAD formation. The effects of TRPCs on TAD were explored in vitro and in vivo. RNA sequencing of thoracic aortas was performed to investigate the mechanism by which TRPCs regulate TAD progression.
RESULTS: Among the TRPC family members, TRPC1 expression was markedly increased in aortas from β-aminopropionitrile-induced TAD mice along with the downregulation of the vascular smooth muscle cell (SMC) contractile markers smooth muscle α-actin and smooth muscle 22. Compared with control littermates, SMC-specific TRPC1 deficiency in mice alleviated β-aminopropionitrile-induced TAD formation characterized by decreased aortic rupture, reduced maximal thoracic aortic diameters, and less elastin degradation. Conversely, SMC-specific knock-in of TRPC1 exacerbated TAD development in mice. Unbiased RNA sequencing showed that TRPC1 knockout in vascular SMCs inhibited the expression of inflammatory factors and chemokines in thoracic aortas during the early stage of β-aminopropionitrile administration. Mechanistically, TRPC1 induced the proinflammatory phenotypic transition of vascular SMCs by activating the calcineurin/nuclear factor-κB pathway, thereby contributing to vascular inflammation and TAD development.
CONCLUSIONS: Our study identified TRPC1 as a novel endogenous pathogenic factor for vascular SMC inflammatory phenotypic transition and TAD formation and provided new insights for a comprehensive understanding of the mechanisms during TAD. Blocking the TRPC1/calcineurin/nuclear factor-κB signaling suppressed TAD progression, which may be a promising strategy to address TAD.
METHODS: Three-week-old male mice were administered β-aminopropionitrile dissolved in drinking water for 28 days to induce TAD formation. The effects of TRPCs on TAD were explored in vitro and in vivo. RNA sequencing of thoracic aortas was performed to investigate the mechanism by which TRPCs regulate TAD progression.
RESULTS: Among the TRPC family members, TRPC1 expression was markedly increased in aortas from β-aminopropionitrile-induced TAD mice along with the downregulation of the vascular smooth muscle cell (SMC) contractile markers smooth muscle α-actin and smooth muscle 22. Compared with control littermates, SMC-specific TRPC1 deficiency in mice alleviated β-aminopropionitrile-induced TAD formation characterized by decreased aortic rupture, reduced maximal thoracic aortic diameters, and less elastin degradation. Conversely, SMC-specific knock-in of TRPC1 exacerbated TAD development in mice. Unbiased RNA sequencing showed that TRPC1 knockout in vascular SMCs inhibited the expression of inflammatory factors and chemokines in thoracic aortas during the early stage of β-aminopropionitrile administration. Mechanistically, TRPC1 induced the proinflammatory phenotypic transition of vascular SMCs by activating the calcineurin/nuclear factor-κB pathway, thereby contributing to vascular inflammation and TAD development.
CONCLUSIONS: Our study identified TRPC1 as a novel endogenous pathogenic factor for vascular SMC inflammatory phenotypic transition and TAD formation and provided new insights for a comprehensive understanding of the mechanisms during TAD. Blocking the TRPC1/calcineurin/nuclear factor-κB signaling suppressed TAD progression, which may be a promising strategy to address TAD.