BMAL1 insufficiency increases the risk of thoracic aortic aneurysm and dissection

Abstract Aims Vascular smooth muscle cell (VSMC) apoptosis plays a key role in the development of thoracic aortic aneurysm and dissection (TAAD), a lethal cardiovascular disease with high mortality rates but limited pharmacological therapy. BMAL1 dysregulation is associated with apoptosis. However, it remains elusive whether BMAL1 dysregulation may aggravate VSMC apoptosis to participate in the development of TAAD. Methods and Results 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 VSMC-specific BMAL1 haploinsufficient mice were used to determine the role of BMAL1 in BAPN-induced TAAD murine model. Transcriptomics, spatial transcriptomics, histological, and in vitro experiments were performed to examine the underlying mechanisms. 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 dysregulation induced VSMC apoptosis during challenge-induced TAAD formation. Moreover, BMAL1 transcriptionally regulated REV-ERBα by binding to the E-box in its promoter region. Overexpression of REV-ERBα alleviated the detrimental effect of BMAL1 dysregulation on the formation of TAAD and VSMC apoptosis. Conversely, REV-ERBα dysregulation aggravated 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 BAPN-induced TAAD in both BMAL1 haploinsufficient and control mice, even when they were administered from 14 days after BAPN modeling. 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.