Receptors for proteins modified by advanced glycation endproducts (AGE)—their functional role in atherosclerosis

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Abstract

Long-term incubation of proteins with glucose leads, through the formation of early stage products such as Schiff base and Amadori rearrangement products, to the formation of advanced glycation end products (AGE). Recent studies of AGE-structures as well as the receptor for AGE-proteins (AGE-receptors) have emphasized the involvement of protein modification by AGE in aging and age-enhanced disease processes. Immunohistochemical analyses of human atherosclerotic lesions using a monoclonal anti-AGE antibody have demonstrated diffuse extracellular AGE-deposition as well as dense intracellular AGE-deposition in macrophage- and vascular smooth muscle cell (SMC)-derived foam cells. In vitro experiments using both CHO cells overexpressing macrophage scavenger receptor-A (MSR-A) and peritoneal macrophages from MSR-A-knockout mice have shown that the MSR-A plays a major role in endocytic uptake of AGE-proteins by macrophages. Furthermore, in vitro experiments with rabbit arterial SMCs demonstrated a novel AGE-receptor mediating endocytosis of AGE-proteins. These in vivo and in vitro experiments suggest that AGE-proteins formed extracellularly in atherosclerotic lesions are endocytosed by macrophages through MSR-A in the early stage, and by SMCs through the novel AGE-receptor in the advanced stage, implicating functional contribution of the AGE-receptor-mediated interaction of AGE-proteins with these cells to atherosclerotic processes in arterial walls.

Introduction

Modification of proteins by long-term incubation with glucose leads, through the formation of early stage products such as Schiff base and Amadori rearrangement products (Maillard, 1912), to the formation of advanced glycation end products (AGE). AGE-modified proteins are characterized physicochemically by fluorescence, brown coloration, and cross-linking, and biologically by specific recognition by the receptors for AGE-modified proteins (AGE-receptors). Three different AGE-receptors have so far been identified; the receptor complex of OST-48, 80K-H and galectin-3 (Li et al., 1996), the receptor for AGE (RAGE) (Neeper et al., 1992, Schmidt et al., 1992) and the macrophage scavenger receptor-A (MSR-A) (Araki et al., 1995, Suzuki et al., 1997). Since the invention of anti-AGE antibodies (Horiuchi et al., 1991, Nakayama et al., 1993), AGE-modified proteins have been demonstrated in several human tissues, implicating a potential link of AGE to aging processes and pathogenesis of diabetic microangiopathy (Vlassara et al., 1994) such as diabetic nephropathy (Makita et al., 1991, Skolnik et al., 1991, Makino et al., 1995), diabetic retinopathy (Yamagishi et al., 1997) and diabetic neuropathy (Yagihashi et al., 1992, Federoff et al., 1993), and other age-enhanced disease processes such as atherosclerosis (Nakamura et al., 1993, Kume et al., 1995), hemodialysis-related amyloidosis (Miyata et al., 1993) and actinic elastosis of photoxidized skins (Mizutari et al., 1997).

Among them, our immunohistochemical approaches using the monoclonal anti-AGE antibody (6D12) demonstrated that AGE-proteins are accumulated in macrophage-derived foam cells in the early stage and SMC-derived foam cells in the advanced stage in human atherosclerotic lesions (Kume et al., 1995). Many cellular experiments have clearly established that AGE-proteins are effectively endocytosed by macrophages or macrophage-derived cells (Vlassara et al., 1985). It was also known that MSR-A, the first receptor cloned among the scavenger receptor family, is preferentially expressed by macrophage-derived foam cells or intimal SMCs in the human atherosclerotic lesions. These data raised the possibility that AGE-proteins formed in situ are recognized by cellular components in atherosclerotic lesions through MSR-A, which may play some role in pathogenesis of atherosclerosis in arterial walls. In the present study, we have focused on the present status of how AGE-modification is potentially related to atherogenesis. In particular, we would like to emphasize the importance of MSR-A in the vascular dysfunction.

Section snippets

The presence of AGE-modified proteins in human atherosclerotic lesions

Our initial study using the monoclonal anti-AGE antibody demonstrated the localization of AGE-proteins in human atherosclerotic lesions in frozen sections of aortas of 25 autopsy cases (Kume et al., 1995). These lesions were divided into diffuse intimal thickening, fatty streak and atherosclerotic plaque; diffuse intimal thickening represents a flat intimal thickening caused by increased fibrous tissues, fatty streak is characterized by flat or slightly elevated lesions with local accumulation

AGE-receptors of macrophages

AGE-proteins are known to undergo the receptor-mediated endocytosis by macrophage and macrophage-derived cells in vitro. Vlassara et al. (1985) were the first to report a receptor-mediated endocytic uptake of AGE-proteins by murine peritoneal macrophages. Independent of this development, we have been interested in the phenomenon of rapid plasma clearance of intravenously injected formaldehyde-modified proteins in rats (Mego et al., 1967). Our results revealed that the rapid plasma clearance was

Future study

To understand the molecular mechanisms of AGE-induced pathogenesis of vasculature and neurons, structural and functional analyses of AGE-binding proteins or AGE-receptors are indispensable. As described in this text and references, many of the AGE-induced cellular responses are demonstrated to be mediated by the AGE-receptors. It is possible that more than two receptors are involved in AGE-induced cellular responses, such as endocytosis, growth-promoting effect and cytokine induction, while

Conclusion

Long-time interaction of AGE-proteins with the AGE-receptors might induce pathogenic effect on cells and tissues. At present, we can not answer which AGE-receptor is the most responsible for AGE-induced pathogenesis of vessels or neuronal cells. However, it seems reasonable to expect that the MSR-A expressed in macrophage-derived foam cells in the early stage of atherosclerotic lesions in arterial walls is involved in AGE-induced atherogenic processes. It does not, of course, rule out the

Acknowledgements

We are grateful to Drs Takayuki Higashi, Kazuyoshi Ikeda, Yoshiteru Jinnouchi, Norie Araki, Takashi Mori, Shuichi Kume, Kiyoshi Takahashi, Hiroshi Suzuki and Tatsuhiko Kodama for their collaborative endeavors. This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan.

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