Abstract 15379: Regulation of Long Non-Coding RNA Fingerprint by Cyclic Mechanical Stretch in Vascular Smooth Muscle Cells: Implications for Aortic Aneurysms
Introduction: Emerging evidence suggests that long noncoding RNAs (lncRNAs) may be a cellular hub for the coordination of cellular processes involved in health and disease. Alterations in the characteristics of vascular smooth muscle cells (VSMCs), triggered largely by changes in mechanical stress, play a critical role in the pathophysiology of vascular diseases like aneurysms and hypertension.
Hypothesis: LncRNAs are involved in mechanical stretch-induced changes in HASMCs.
Methods: Total RNA was extracted with TRIzol. LncRNAs and mRNAs were profiled with the Arraystar Human LncRNA Microarray V3.0. Aneurysmal and non-aneurysmal samples were collected from patients undergoing aortic arch repair and the aortas of ApoE-/- mice infused for 4 weeks with angiotensin II or saline. Gene expression was quantified via qRT-PCR. For knockdown studies, HASMCs were transfected with 10 nM siLincRNA-p21 or 5 nM scrambled control (nM). Apoptosis was assessed using Annexin V/PI double staining.
Results: Of the 30,586 human lncRNAs screened in HASMCs, 580 were differentially expressed (P < 0.05) in the stretched vs. static group. Human long intergenic non-coding RNA-p21 was significantly upregulated in stretched HASMCs (N = 3, P < 0.05) and human aneurysmal samples (N = 10, P < 0.05). The murine homolog of lincRNA-p21 was upregulated in aortic tissues from angiotensin-II-infused ApoE-/- mice (N = 3, P < 0.05). Apoptosis was decreased in stretched HASMCs silenced with lincRNA-p21 (N = 3, P < 0.05). Silencing of lincRNA-p21 also decreased the expression of the p53-downstream genes Bax, Puma, Noxa, and Mdm2 under conditions of stretch (N = 3, P < 0.05).
Conclusions: We describe the first transcriptome profile of stretch-induced changes in HASMCs. The data implicate lincRNA-p21 as a mechanoresponsive regulator of aneurysm formation in mice and humans, and provide novel insights into the regulatory switches governing aberrant VSMC remodeling, which may have importance in the pathogenesis of aneurysms and hypertension.
Author Disclosures: L. Mantella: None. K.K. Singh: None. P. Sandhu: None. C. Kantores: None. A. Ramadan: None. N. Khyzha: None. A. Quan: None. M. Al-Omran: None. J.E. Fish: None. R.E. Jankov: None. S. Verma: None.
- © 2016 by American Heart Association, Inc.