Abstract 539: MicroRNA-27b Regulates Salt-Inducible Kinase 1 (SIK1) in Vascular Fibrosis
Arterial fibrosis is one of the main underlying causes of vascular stiffness and various associated diseases, such as hypertension, congestive heart failure, aortic aneurysm development and renal failure. Consequently there is a growing interest in (patho)-mechanisms governing the underlying process of arterial fibrosis and successive vascular stiffness. Recently, a novel class of small noncoding RNAs, termed microRNAs (miRs), have emerged as powerful cellular regulators in disease processes. Furthermore, they have become an intriguing target for therapeutic intervention. Aim of the present study was to explore whether miRs are regulating the expression of salt-inducible kinase 1 (SIK1), which we previously identified as a crucial regulator of fibrosis in heart-/kidney- failure and arterial hypertension.
Using different bioinformatic target prediction algorithms, we identified several miRs with predicted conserved sites on the Sik1 gene, including miRs-27a/b, -130a, -148a/b and -152. By analyzing aorta, heart and kidney specimen from Sik-/- and Sik+/+ mice, we were able to detect that miR-27b was the only miR being significantly altered in all three tissues. We proceeded by treating human aortic smooth muscle cells as well as adventitial fibroblasts with TGF-β, to induce a pro-fibrotic response. Interestingly, treatment with TGF-β substantially increased miR-27b expression as well as other components of the extracellular matrix, such as collagen (Col1a1) and fibronectin (Fn1) through repression of SIK1. Overexpression of miR-27b, utilizing a pre-miR precursor, substantially decreased SIK-1 expression and further augmented the pro-fibrotic response, as indicated by raising collagen and Fn1 expressions.
The present study explores the regulatory role of miR-27b in different vascular fibrosis associated pathologies. We were able to show that miR-27b, a novel downstream-target of TGF-β signalling pathways, suppresses the expression of SIK1, which itself has been identified as a key regulator of arterial hypertension and consequential heart and kidney failure. On-going studies, utilizing inhibition of miR-27b can become an interesting novel therapeutic strategy to regulate SIK1 levels in vascular fibrosis and arterial stiffness.
- © 2013 by American Heart Association, Inc.