Cholesterol enriched diet suppresses ATF6 and PERK and upregulates the IRE1 pathways of the unfolded protein response in spontaneously hypertensive rats: Relevance to pathophysiology of atherosclerosis in the setting of hypertension.

Many studies have been dedicated to hypertension and hypercholesterolemia, as they are the primary conditions that influence the unfolded protein response (UPR). However, the concurrent effects of these two factors are unknown. Our research used spontaneously hypertensive rats (SHR) fed a cholesterol enriched diet (CED) as model of atherosclerosis formation to discover what effect the simultaneous actions of hypertension and hypercholesterolemia have on the UPR. The combination of hypertension and consumption of a CED (not the CED alone) caused the formation of early atherosclerotic features. Both increased expression of the CCAAT-enhancer-binding protein (CHOP) and the insulin induced gene 1 (INSIG1), which is the target gene of the sterol regulatory element-binding protein 1-c (SREBP1-c), and decreased expression of the spliced x-box binding protein1 (sXBP1) mRNA were observed in the SHR fed a CED. Cholesterol overload strongly suppressed glucose regulated protein 78 (GRP78), glucose regulated protein 94 (GRP 94), and the expression of CHOP and INSIG1 mRNA in both normotensive and hypertensive rats. Unlike other UPR factors, the sXBP1 mRNA expression was strongly downregulated in SHR fed a normal diet but upregulated in those fed a CED. The changes to UPR in the SHR fed a CED were associated with improvement of the initially impaired heart function of the rats.