Abstract 463: The Smooth-Muscle-Cell-Angiotensin II-Sensitive LncRNA Controls Cell Division Fidelity And Mitochondrial Organization

Abstract

Reactivation of the cell cycle and increase in proliferation rate (hyperplasia) is a common response of vascular smooth muscle cells (SMC) to modifications of their environment during remodeling. Although SMC hyperplasia is a predominant feature of many vascular diseases, SMC can also increase their mass within the remodeled vessel wall by enlarging their size and becoming hypertrophic. Hypertrophy is usually accompanied by cell cycle defects, cell polyploidy and binucleation, and senescence. However, the molecular mechanisms favoring SMC hypertrophy and their repercussion on SMC phenotype are not fully understood. Long-non-coding-RNAs (LncRNAs) are epigenetic regulators of gene expression, and they have been identified as modulators of cell division. We recently discovered a novel lncRNA, SAS (SMC-Angiotensin II-Sensitive), whose expression was markedly decreased in multiple models of SMC dedifferentiation, suggesting that SAS could regulate SMC phenotype and function. Publicly available transcriptional datasets revealed that SAS is preferentially expressed in SMC-rich tissues, including the aorta, in humans and mice. Yet, the functional relevance of SAS in SMC has never been investigated. Knockdown of SAS reduces proliferation, cell arrest and migration in aortic and renal artery-derived SMC treated with Platelet Derived Growth Factor. SAS knockdown was also associated with distinct SMC morphological changes including increase in cell size and binucleation demonstrating hypertrophy. Together, these observations suggest that decrease in SAS causes SMC hypertrophy due to defects in cell cycle completion and cytokinesis. Interestingly, SAS expression is decreased in response to Angiotensin-II in cultured VSMC and in the aorta of hypertensive mice (2 Kidney-1 Clip model), suggesting a role in mediating hypertension induced SMC hypertrophy. Similarly, to Angiotensin-II treatment, SAS knockdown promoted senescence. Furthermore, SAS deficient cells present mitochondria hyperfusion and increased oxygen consumption that correlates with the observed exacerbated senescence. Altogether, our results indicate that SAS is a potent regulator of VSMC morphology and is required for proper cell division and mitochondria organization.