Abstract 18975: Increased Arterial Blood Pressure and Vascular Fibrosis/remodeling in Mice Lacking Salt-inducible Kinase 1 (sik1)

Abstract

Arterial fibrosis is one of the main underlying causes of vascular stiffness and is increasingly recognized as an important prognostic factor in the development of high blood pressure (BP), yet its physiophatology is not fully known. Therefore, elucidating the precise mechanism leading to arterial fibrosis will help improving current anti-hypertensive therapies. We previously described in human genetic studies a single nucleotide polymorphism within the salt-inducible kinase 1 (SIK1) gene, affecting the activity of the protein, which is associated with hypertension (lower SIK1 activity is associated with higher BP). Also, lower SIK1 expression induces the expression of transcription factors commonly involved in fibrosis. Therefore, we hypothesized that SIK1 can regulate BP by reducing vascular fibrosis and hence vascular stiffness. To test this, BP and aortic wall structure/composition was evaluated in sik1 -/- and sik1 +/+ mice challenged with a chronic high salt (HS) or normal salt diet (NS). The results showed that the s ik1 -/- mice challenged with HS developed high BP and presented signs of cardiac hypertrophy (increased left ventricle wall thickness and enhanced expression of hypertrophic genes) when compared to their counterparts on NS. On the contrary, BP and cardiac parameters remained unaffected in the sik1 +/+ mice under HS when compared to NS fed mice. Immunohistochemistry analysis revealed increased intima/media thickness and collagen deposition in the aorta of the sik1 -/- vs. sik1 +/+ mice under NS and before becoming hypertensive. Also, qPCR analysis of the aorta of the sik1 -/- mice showed increased expression of other extracellular matrix (ECM) components such as fibronectin and laminin-β1. In addition, the transient knock-down of the SIK1 gene in vascular smooth muscle cell (VSMC) cultures using siRNAs showed a similar increase in the expression of collagen as well as other ECM genes. The present study shows that SIK1 activity is necessary to prevent the development of hypertension, possibly through an anti-fibrotic mechanism regulating vascular wall structure and function. Therefore, SIK1 could become a novel therapeutic target in the treatment of hypertension and other vascular fibrosis-associated diseases.