Abstract 325: Cardiac Hypertrophy in Spontaneous Hypertensive Rats (SHR) is Associated With Decreased Cardiac Expression of SIK1 and SIK3 Isoforms
Numerous reports have highlighted the importance of protein kinases and transcription factors in cardiogenesis and cardiac hypertrophy. The salt-inducible kinase 1 (SIK1), a protein kinase encoded by the snf1lk gene, is involved in early cardiogenesis in mice. Genotype-phenotype association studies in three Swedish and one Japanese population-based cohorts suggested that 15Ser-SIK1 variant (15Gly-Ser change, T allele), bestow augmented SIK1 activity, was associated with lower blood pressure and decreases in left ventricular (LV) mass. The present study aims to determine the potential role of SIK1 as a mediator of cardiac hypertrophic signaling pathway and to evaluate age-related changes on the cardiac expression of several elements of the SIK network associated with hypertension, in Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR). For this purpose, mRNA expression levels of skeletal actin (SkA), β-myosin heavy chain (β-MHC) and matrix metalloproteinase-9 (MMP-9) as markers for cardiac hypertrophy, SIK isoforms (SIK1, SIK2 and SIK3), and transcription factors (MEF2C, NFAT5c, KFL4, Snail1 and Snail2) were determined, using Taqman, in 13- , 52- and 91-week old SHR and their normotensive counterparts WKY. Systolic and diastolic blood pressures, determined by the tail-cuff method, were significantly higher in 3- , in 3- , 13- and 21-month old SHR than in age-matched WKY. In the SHR, increases in heart/tibia length ratio were associated to the overexpression of cardiac hypertrophic genes (SkA and β-MHC) and the underexpression of cardiac SIK3, at the age of 3- , 13- and 21-months. Ageing accompanied by a diminished mRNA expression of SIK1 in SHR, relative to WKY (both at 13- and 21-months of age). Whereas, Snail2, MFAT5c and KLF4 mRNA levels decreased with aged SHR, comparing to age-match WKY (both at 13- and 21-months of age). These results indicate that SIK1 and SIK3 isoforms might be upstream mediators of transcriptions factors implicated in the regulation of cardiac hypertrophic growth response. In conclusion, ageing in SHR is accompanied by cardiac alterations that include hypertrophy and dysfunction of the SIK signaling network. Supported by grant PIC/IC/83204/2007.
- © 2012 by American Heart Association, Inc.