BMAL1 insufficiency increases the risk of thoracic aortic aneurysm and dissection

Background Thoracic aortic aneurysm and dissection (TAAD) has a high mortality rate with limited pharmacological therapy. BMAL1 insufficiency is associated with cardiovascular risks. However, the association between BMAL1 insufficiency and the development of TAAD remains elusive. Purpose To investigate the role of BMAL1 in the development of TAAD. Methods Transcriptomic analysis and molecular assays were performed to analyze BMAL1 level in the TAAD patients and 3-aminopropionitrile fumarate (BAPN)-induced TAAD mice. Global and vascular smooth muscle cell (VSMC)-specific BMAL1 haploinsufficient mice were used to determine the role of BMAL1 in BAPN-induced TAAD murine model. Transcriptomic, spatial transcriptomic analysis, histological, and in vitro experiments were performed to examine the underlying mechanisms. Results BMAL1 level was reduced in the thoracic aorta from TAAD patients and BAPN-challenged mice. Global and VSMC-specific BMAL1 haploinsufficiency significantly increased the risk of BAPN-induced TAAD in mice. BMAL1 insufficiency induced VSMC apoptosis during challenge-induced TAAD formation. Moreover, REV-ERBα was verified to be downstream of BMAL1 to regulate VSMC apoptosis. Rev-erbα knockout enhanced the susceptibility to TAAD and aggregated VSMC apoptosis. Overexpression of REV-ERBα reversed the detrimental effect of BMAL1 insufficiency on the formation of TAAD and VSMC apoptosis. Mechanistically, VSMC apoptosis inducer c-MYC was regulated by BMAL1/REV-ERBα axis and was proven as a direct target of REV-ERBα. Importantly, BMAL1 activator ISX-9 and REV-ERBα agonist SR9009 reduced the risk of TAAD in both BAPN-challenged BMAL1 haploinsufficient and control mice. Conclusions BMAL1 insufficiency increases the risk of TAAD by inducing VSMC apoptosis via downregulation of REV-ERBα. BMAL1 and REV-ERBα may serve as pharmacological targets for TAAD prevention and therapy.