Abstract 379: Smooth Muscle-specific Lncrna Carmn Plays A Potential Role In Aortic Aneurysm

Background: Aortic aneurysm is a life-threatening vascular disease characterized by vascular smooth muscle cell (VSMC) depletion, ECM degradation, and infiltration of immune cells. Previous studies have shown that Carmn , a SMC-enriched long non-coding RNA, is critical for maintaining VSMC contractile phenotype. However, its functional role in aortic aneurysm remains completely unknown. Methods and Results: We re-analyzed the publicly available aortic aneurysm bulk RNA-seq and scRNA-seq datasets in mouse and human. These unbiased analyses revealed that Carmn is downregulated in the SMCs of aortic aneurysm samples. To examine the potential role of Carmn in aortic aneurysm, we generated Carmn global knockout (gKO) mice or inducible SMC-specific KO (iKO) mice driven by Myh11 -Cre ER T2, respectively. Unexpectedly, both Carmn gKO and iKO mice exhibited premature lethality, due to a severe colonic pseudo-obstruction resulting from deletion of Carmn in visceral SMCs. Despite the dominant gastrointestinal phenotype observed in Carmn KO mice, morphological analysis of the Carmn KO thoracic aorta revealed thinner vascular wall compared to that of controls. Results from TEM showed that the VSMC in the Carmn KO thoracic aorta are disorganized and degradative with aneurysmal dissection. Data from bulk RNA-seq of Carmn -deficient aorta revealed that the down-regulated genes are associated with degradation of ECM while the up-regulated genes are associated with cell death. Moreover, scRNA-seq of Carmn -deficient aorta revealed that the percentage of the SMCs is decreased while the percentage of infiltrated immune cells is increased. These data indicated that Carmn deficiency may play a critical role in promoting the development of aortic aneurysm. To circumvent the lethal visceral SMC phenotype, we are in the progress of crossing Carmn flox mice with the novel vascular SMC-specific inducible Itga8 -Cre ER T2 mouse to generate VSMC-specific Carmn KO mice. Conclusions: Our data suggest that Carmn is indispensable for maintaining gastrointestinal contractile function, and implicate that Carmn deficiency plays a potential role in contributing the development of aortic aneurysm.