The Role of Salt Inducible Kinase-2 in the Development of Cardiovascular Disease. (360G-Wellcome-207358_Z_17_Z)

Development of Cardiovascular Disease (CVD) is preceded by endothelial dysfunction, inflammation and infiltration of vessel walls by pro-inflammatory leukocytes, resulting in formation of atherosclerotic plaques. Recent in vivo studies have suggested a role for the Salt Inducible Kinase-2 (SIK2) enzyme in regulation of inflammatory cytokine production. SIK2 phosphorylates CRTC3, promoting cytosolic retention. Inhibition of SIK2 prevents CRTC3 sequestration and promotes nuclear accumulation where it associates with CREB and promotes transcription of IL-10, IL-1ra and the anti-atherosclerosis associated gene, Nur77. Furthermore, macrophages from SIK2 kinase-null mice produce significantly less pro-inflammatory IL-6, IL-12 and TNF-a. The precise role of SIK2 in CVD is unknown. Using femoral artery cross-sections and subcutaneous blood vessels collected from diabetic humans following elected above knee amputations, we aim to characterise the expression and function of SIK2 in the development of atherosclerosis. Furthermore, we aim to compare these findings with blood biomarkers of inflammation and kidney function. Expression of SIK2 shall be investigated using RT-PCR gene expression analysis and related to enzyme function using western blot analysis of protein phosphorylation, focussing on the TLR4-MAPK-MSK-CREB-CRTC3 signalling axis. Identification of SIK2 as a regulator of atherosclerotic development could provide a novel drug target for the prevention and management of CVD.