Genetic Regulation of Circular RNA Expression in Human Aortic Smooth Muscle Cells and Vascular Traits

Abstract

Background: Circular RNAs (circRNAs) are a class of non-coding RNAs that have cell-type specific expression and are relevant in cardiovascular disease. Aortic smooth muscle cells (SMCs) play a crucial role in cardiovascular disease by differentiating from a quiescent to proliferative phenotype. The role of circRNAs in SMCs and their relevance to cardiovascular disease is largely unexplored. Results: In this study, we employ a systems genetics approach to identify circRNA transcripts at a genome wide level and their relevance in cardiovascular traits. We quantified circRNA expression across 151 quiescent and proliferative human aortic SMCs from multiethnic donors. We identified 1,589 expressed circRNAs. Between quiescent and proliferative SMCs, we identified 173 circRNAs which were differentially expressed. To characterize the genetic regulation of circRNA expression, we associated the genotypes of 6.3 million single nucleotide polymorphisms (SNPs) with circRNA abundance and found 96 circRNAs which were associated with genetic loci. Three SNPs were associated with circRNA expression in proliferative SMCs but not in quiescent SMCs. We identified 6 SNPs which had distinct association directions with circRNA isoforms from the same gene. Lastly, to identify the relevance of circRNAs in cardiovascular disease, we overlapped genetic loci associated with circRNA expression with vascular disease related GWAS loci. We identified 7 blood pressure, 1 myocardial infarction, and 3 coronary artery disease loci which were associated with a circRNA transcript (circZKSCAN1, circFOXK2, circANKRD36, circLARP4, circCEP85L, circGTF3C2, circPDS5A, circSLC4A7, and chr17:42610108|42659552) but not mRNA transcript. Conclusions: Overall, our results provide mechanistic insight into the regulation of circRNA expression and the genetic basis of cardiovascular disease.

Enhancer of zeste homolog 2 facilitates phenotypic transition of vascular smooth muscle cells leading to aortic aneurysm/dissection

“…The phenotypic transition of VSMCs is characterized by decreased expression of contractile markers, a key event contributing to VSMC proliferation and migration (14). Thus, the effect of Ezh2 on phenotypic VSMC switching was assessed.…”

“…The ECM provides tensile strength and elasticity to vessel walls and regulates several processes, including proliferation, migration, differentiation and adhesion of VSMCs (3,6). An imbalance between anabolic (ECM synthesis) and catabolic (ECM degradation) phases in the composition of the ECM can result in the development of aortic aneurysms (14).…”