The role of glucosamine-induced ER stress in diabetic atherogenesis

Abstract

Cardiovascular disease (CVD) is the major cause of mortality in individuals with diabetes mellitus. However the molecular and cellular mechanisms that predispose individuals with diabetes to the development and progression of atherosclerosis, the underlying cause of most CVD, are not understood. This paper summarizes the current state of our knowledge of pathways and mechanisms that may link diabetes and hyperglycemia to atherogenesis. We highlight recent work from our lab, and others', that supports a role for ER stress in these processes. The continued investigation of existing pathways, linking hyperglycemia and diabetes mellitus to atherosclerosis, and the identification of novel mechanisms and targets will be important to the development of new and effective antiatherosclerotic therapies tailored to individuals with diabetes.

Figure 1

The unfolded protein response to endoplasmic reticulum stress. ER stress occurs when the capacity of the ER to process/fold proteins is exceeded by the load of nascent proteins entering the ER. The function of the UPR is to reestablish ER homeostasis by decreasing protein flux into the ER (translation block) while increasing the folding capacity of the ER (increased chaperone expression). Conditions of ER stress lead to the dissociation of ER chaperone GRP78 from the trans-ER-membrane signaling factors PERK, IRE1, and ATF6, resulting in their activation. Activated PERK phosphorylates and inhibits the activity of eIF2α, an essential factor in general protein translation. PERK is also involved with the downstream activation of transcription factors including ATF4 and GADD153. Activated IRE1 assists in the alternative splicing of XBP-1 resulting in the translation of a transcription factor, XBP-1, which is involved in upregulation of the expression of ER chaperones. Activated ATF6 translocates to the Golgi where proteases S1P and S2P release an N-terminal transcription activation domain that works in concert with XBP-1 to upregulate ER chaperone expression.

Figure 2

Analysis of aortic root from normoglycemic, STZ-injected hyperglycemic, and STZ-injected insulin-treated ApoE^−/− mice. Hyperglycemic mice show increased vascular O-linked GlcNAc, elevated levels of ER stress markers (GRP78/94), and significantly accelerated atherosclerotic lesion development, relative to normoglycemic controls. Normalization of glucose levels with insulin attenuates O-GlcNAc accumulation, ER stress, and atherogenesis.

Figure 3

Working model of diabetes-associated accelerated atherothrombosis. Chronic hyperglycemia leads to increased flux through the hexosamine biosynthesis pathway (HBP) resulting in accumulation of UDP-N-acetylglucosamine (UDP-GlcNAc), a substrate for both O- and N-linked protein glycosylation, as well as increased levels of ER stress. Disruptions in ER homeostasis lead to activation of the unfolded protein response (UPR) and downstream effects including activation of glycogen synthase kinase (GSK)-3. Our results suggest that ER-stress-induced GSK-3 induces proatherogenic processes leading to the accelerated development of atherothrombosis.