Abstract 4139822: Adipocyte TRPM7 promotes aortic dissection by accelerating SMC phenotype switching

Background: Aortic dissection (AD) is a life-threatening condition with high mortality. It initiates from an acute intimal tear, which allows a large amount of blood to penetrate into media, leading to the formation of intramural hematoma or false lumen. Digging into and unravelling the pathogenesis of AD will aid in exploring novel therapeutics for AD. The major characteristics of AD is degeneration of aortic wall architecture. Particularly, the phenotypic switching of VSMCs and enhanced tissue inflammation are pivotal steps of AD progression. Studies have shown that upregulation of Trpm7 triggers the phenotypic switching of VSMCs. Perivascular adipose tissue (PVAT) harbors mature adipocytes that regulate vascular function physiologically and pathologically. Inflammatory cytokines secreted from PVAT promotes VSMC phenotypic switching. This study aims to explore whether the adipocyte TRPM7-mediated Ca2+ could uncouple Bip-IRE1a and perturb the inhibition of Bip on IRE1a, inducing PCG1a mRNA decay and inflammatory cytokines secretion, thus promoting VSMC phenotypic switching and the development of AD. Methods: Mouse breeding. Trpm7fl/fl mice were cross-bred with Ap2-Cre mice to generate adipocyte-specific Trpm7 KO mice. Mouse genotyping. Genomic DNA was extracted from the mouse tail for PCR to validate the genotype of mice. Establishment of BAPN-induced TAD mouse model. 3-week-old mice was administered with BAPN intragastrically (1g/kg/day) for 4 weeks. H&E staining. Different segments of mouse aorta were subjected to H&E staining to examine the lesions. EVG staining. Different segments of mouse aorta were subjected to EVG staining to examine the aortic wall architecture. Real-time quantitative PCR (qPCR). The expression level of inflammatory genes and VSMC contractile genes, including IL1b, TNF-a, Acta2, Cnn1, Tagln, S100A4, as well as Trpm7 were assessed by qPCR. Results: Adipocyte-specific Trpm7 KO mice (Trpm7fl/fl ; Ap2-Cre ) were successfully generated and each genotype was validated by PCR. BAPN-induced TAD mouse model was successfully established. The mortality rate reached to 50-80%. Adipocyte-specific deletion of Trpm7 hindered inflammation and the development of TAD effectively. Trpm7 inhibitors FTY720 hindered the progress of TAD significantly. Conclusion: Adipocyte-specific deletion of Trpm7, as well as Trpm7 blockers FTY720 markedly ameliorates TAD, suggesting that Trpm7 enhances TAD progression.