Original article
Upregulation of the ligand–RAGE pathway via the angiotensin II type I receptor is essential in the pathogenesis of diabetic atherosclerosis

https://doi.org/10.1016/j.yjmcc.2007.07.044Get rights and content

Abstract

The receptor for advanced glycation end products (RAGE) and the angiotensin II type I receptor (AT1R) have been separately linked to the pathogenesis of diabetic atherosclerosis. However, no prior study has addressed a linkage between RAGE and AT1R in diabetic atherogenesis. Therefore, we tested the hypothesis that upregulation of the ligand–RAGE axis via AT1R is an essential process underlying the disease. Diabetes was induced in apolipoprotein E-deficient (ApoE−/−) mice by streptozotocin, and diabetic mice were treated with AT1 receptor blocker (ARB) for 6 weeks. Diabetic ApoE−/− mice that were AT1R-deficient (ApoE−/−AT1aR−/−) were also investigated. In diabetic ApoE−/− mice, AT1R was found to increase within 1 week of diabetes induction, before ligand–RAGE pathway activation and other inflammatory changes were observed. Both ARB treatment and AT1aR deficiency suppressed diabetic atherosclerosis, ligand–RAGE expression and inflammatory changes. In contrast, upregulation of the ligand–RAGE pathway was noted in atherosclerotic plaques from non-diabetic ApoE−/− mice infused with angiotensin II. In cultured vascular smooth muscle cells, angiotensin II increased RAGE protein levels via AT1R stimulation. Upregulation of the ligand–RAGE pathway via AT1R is an essential mechanism in diabetic atherosclerosis, implying that ARB might decrease diabetic atherogenesis by inhibiting ligand–RAGE signals.

Introduction

Diabetes mellitus affects more than 100 million people worldwide, and the incidence of type 2 diabetes is likely to increase as a result of lifestyle patterns leading to obesity and metabolic syndromes [1]. This point is clinically important because type 2 diabetes is associated with accelerated atherosclerosis and a higher risk of cardiovascular disease [2], [3]. Furthermore, intensive glycemic control may not totally prevent cardiovascular disease in diabetic patients [4], [5], [6]. In addition to good glycemic control, lifestyle modification and aggressive treatment of associated risk factors are recommended [7]. The mechanisms underlying diabetes-induced acceleration of atherosclerosis remain to be fully elucidated. Recent studies have reported that angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin II type 1 (AT1) receptor blocker (ARB) suppress diabetes-induced acceleration of atherosclerosis in experimental animals [8], [9] and reduce the risk of future cardiovascular events in diabetic patients [10], [11]. However, the precise mechanism by which ACE-I and ARB reduce diabetic atherogenesis remains to be fully addressed.

Recent studies have provided ample evidence indicating that the receptor for advanced glycation end products (RAGE) and its ligands play a central role in diabetic atherogenesis [12], [13], [14]. Atherosclerotic plaques from diabetic patients exhibit greater expression of RAGE and its ligands and have higher levels of inflammation and apoptosis than those from non-diabetic patients [15], [16]. Furthermore, blocking or genetically deleting RAGE in experimental animals was markedly effective in suppressing the initiation of early atherosclerosis, the progression of advanced atherosclerosis and the plaque destabilization [12], [13]. Taken together, these prior studies support the concept that upregulation of the ligand–RAGE pathway resulting in inflammatory changes is a pivotal step in the mechanism of diabetic atherosclerosis. Because activated macrophages and smooth muscle cells may express RAGE and the AT1 receptor (AT1R), it is reasonable to ask whether there is a meaningful linkage between RAGE and AT1R. However, no prior study on the mechanism of diabetic atherogenesis has addressed this possible linkage.

Therefore, the aim of this study was to test the hypothesis that upregulation of the ligand–RAGE pro-inflammatory axis via AT1R is an essential mechanism in diabetic atherosclerosis. Several groups have demonstrated that streptozotocin-induced diabetes in apolipoprotein E-deficient (ApoE−/−) mice results in accelerated atherosclerosis with destabilization phenotypes resembling those observed in humans. In this mouse model, diabetic atherogenesis has been attributed to RAGE and its ligands [12], [13]or to AT1R [8], [9]. Thus, we used this model to investigate a possible linkage between RAGE and AT1R.

Section snippets

Experimental animals

Male ApoE−/− mice were purchased from Jackson Laboratory (Bar Harbor, ME). ApoE−/−AT1aR−/− mice with the same genetic background (C57BL/6J) were created by crossing ApoE−/− and AT1aR−/− mice. The study protocol was reviewed and approved by the Committee on the Ethics of Animal Experiments, Kyushu University Graduate School of Medical Sciences.

Animal models

Animals were maintained on a 12-h light–dark cycle with free access to rodent chow and water. At 9 weeks of age, mice were rendered diabetic by

Both ARB treatment and AT1aR deficiency limit diabetic acceleration of atherosclerosis

Streptozotocin-induced diabetes accelerated atherosclerotic lesion formation in ApoE−/− mice, as reported previously [23]. Treatment with ARB (telmisartan or olmesartan) limited the diabetes-induced acceleration of atherosclerosis (Fig. 1). Interestingly, AT1aR−/− mice displayed similar suppression of diabetic atherosclerosis (Fig. 1). Diabetic atherosclerosis exhibits complex lesions characterized by increased lipid composition and macrophage infiltration, which may increase vulnerability to

Discussion

Prior studies have demonstrated that treatment with ACE-I or ARB attenuates the development of diabetic atherosclerosis in ApoE−/− mice [8], [9] and reduces atherosclerotic vascular events in diabetic patients [10], [11], indicating the importance of the renin-angiotensin system in diabetic atherogenesis. However, in the case of pharmacological blockers, non-specific actions cannot be ruled out. Therefore, the novel finding of this study is that in addition to ARB treatment, genetic deletion of

Acknowledgments

This study was supported by Grants-in-Aid for Scientific Research (14657172, 14207036) from the Ministry of Education, Science, and Culture, Tokyo, Japan; Health Science Research Grants (Research on Translational Research) from the Ministry of Health Labor and Welfare, Tokyo, Japan; and the Program for Promotion of Fundamental Studies in Health Sciences of the Organization for Pharmaceutical Safety and Research, Tokyo, Japan.

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