Analysis of Intimal Proteoglycans in Atherosclerosis-prone and Atherosclerosis-resistant Human Arteries by Mass Spectrometry

Abstract

The propensity to develop atherosclerosis varies markedly among different sites in the human vasculature. To determine a possible cause for such differences in atherosclerosis susceptibility, a proteomics-based approach was used to assess the extracellular proteoglycan core protein composition of intimal hyperplasia from both the atherosclerosis-prone internal carotid artery and the atherosclerosis-resistant internal thoracic artery. The intimal proteoglycan composition in these preatherosclerotic lesions was found to be more complex than previously appreciated with up to eight distinct core proteins present, including the large extracellular proteoglycans versican and aggrecan, the basement membrane proteoglycan perlecan, the class I small leucine-rich proteoglycans biglycan and decorin, and the class II small leucine-rich proteoglycans lumican, fibromodulin, and prolargin/ PRELP (proline arginine-rich end leucine-rich repeat protein). Although most of these proteoglycans seem to be present in similar amounts at the two locations, there was a selective enhanced deposition of lumican in the intima of the atherosclerosis-prone internal carotid artery compared with the intima of the atherosclerosis-resistant internal thoracic artery. The enhanced deposition of lumican in the intima of an atherosclerosis prone artery has important implications for the pathogenesis of atherosclerosis.

Expression of fibromodulin in carotid atherosclerotic plaques is associated with diabetes and cerebrovascular events

“…17 In addition, lumican has been shown to be expressed in intimal vascular SMCs in human coronary atherosclerosis 18 and, as compared to arteries from healthy subjects, overexpressed in arteries from patients with coronary artery dis-ease, 19 in femoral arteries with atherosclerotic plaques from patients with peripheral occlusive arterial disease 20 and in aortic valves from patients with degenerative aortic stenosis 21 .…”

“…Our previous results suggesting that fibromodulin is involved in plaque development by affecting ECM structure and lipid retention, together with previous publications discussing lumican expression in healthy and pathological vasculature, [17][18][19][20][21] raise the question of possible contribution by these SLRPs to atherosclerotic plaque development and its stability. In the present study we have thus for the first time analyzed the expression of fibromodulin and lumican in human carotid plaques in relation to the occurrence of preoperative cerebrovascular symptoms (namely strokes, transient ischemic attacks (TIA) or amaurosis fugax) and postoperative cardiovascular (CV) events.…”

Inflammatory Cell Infiltrates in Vessels With Different Susceptibility to Atherosclerosis in Rheumatic and Non-Rheumatic Patients A Controlled Study of Biopsy Specimens Obtained at Coronary Artery Surgery

“…[22][23][24] The development of atherosclerosis may depend on both systemic factors (eg, traditional cardiovascular risk factors, dysregulation of the immune system, or infection) and local vascular factors such as the biochemical structure, the presence and characteristics of the immunoactive cells, neurohumoral regulation, or microcirculation of the vessel. 10,[25][26][27][28][29][30][31] Not only the intima, but also the deep vascular layers may play a substantial role in plaque formation. 21,[32][33][34][35] We note that the MCIs were localized diffusely in the fibrofatty tissue and/or around the vasa vasorum.…”

Subendothelial Lipoprotein Retention as the Initiating Process in Atherosclerosis

“…[3][4][5]11 Of interest, a recent study comparing intimal proteoglycans in atherosclerosis-susceptible versus -resistant regions of the human arterial tree showed enhanced deposition of a CS-containing proteoglycan called lumican in the susceptible regions. 90 The key advance in establishing causality between lipoprotein-CS interaction and early atherogenesis came from a series of studies in mice expressing apoB-100 with sitedirected mutations in its CS-binding region. 9,91 The study was designed to ensure that any differences in atherosclerosis were due to weak binding of the mutated apoB-containing LDL to proteoglycans, not to some other attribute of the mutated LDL such as the inability to bind to LDL receptors.…”