Cold exposure increases aortic dissection risk through extracellular cold inducible RNA binding protein and toll like receptor 4 signaling

Several observational studies have indicated a greater risk of cardiovascular diseases in cold weather. Cold-inducible RNA-binding protein (CIRP) is highly conserved and upregulated in response to various cellular stressors. Although CIRP provides protective effects against cold exposure, extracellular CIRP (eCIRP) is a danger-associated molecular pattern that can trigger inflammatory response. We aimed to explore the association between cold temperature and AD development, decipher the mechanistic links between cold stress and vascular cell injury, and provide a new therapeutic approach for cold stress-induced vascular emergencies. We used daily meteorological records obtained from the Taiwan Central Weather Administration and health insurance claims from the National Health Research Institute to examine the association between cold temperature and AD development. A murine AD model was established via treatment with the irreversible lysyl oxidase inhibitor 3-aminopropionitrile fumarate (BAPN). The mice were subjected to acute cold exposure (ACE) at 4 ± 1 °C. We found that cold stress and exogenous CIRP induced vascular inflammation and the overexpression of matrix metalloproteinase-2 through the Toll-like receptor 4 (TLR4) pathway in endothelial cells in vitro. There was a greater risk of AD at cold temperatures. ACE increased the aortic arch diameter and circulating CIRP and interleukin-6 levels in BAPN-fed, AD-susceptible mice. Exogenous recombinant CIRP exacerbated AD in BAPN-treated mice. C23, a competitive CIRP antagonist, ameliorated ACE-exacerbated AD in BAPN-treated mice. In conclusion, cold temperatures are associated with AD development in a subtropical/tropical monsoon climate. Cold stress could exacerbate AD development through the eCIRP/TLR4 pathway. Blocking eCIRP prevented cold-induced exacerbation of AD in AD-susceptible mice.