The Response-to-Retention Hypothesis of Early Atherogenesis

Abstract

This idea is related to the lipid infiltration hypothesis, 5 which originated with Anichkov and Khalatov 28 (reviewed in References 29 and 30 29, 30). Alterations in permeability or even microscopic losses of endothelial cells in excess of those due to normal cell turnover are not mechanistically required for atherogenesis, however, because normal, healthy endothelium transports 31, 32 or "leaks" 26, 33 many molecules, including lipoproteins (reviewed in Reference 27 27). In fact, the rate of LDL entry into the normal, healthy arterial wall vastly exceeds the LDL accumulation rate. 34 Most important, seminal studies by Schwenke and Carew 35, 36 showed in vivo that the early prelesional accumulation of atherogenic lipoproteins within the arterial wall is focally concentrated in sites that are known to be prone to the later development of atheromata, but that the rates of lipoprotein entry into prelesional susceptible versus resistant sites were not different (cf Reference 2 2). These studies indicate that retention, not enhanced endothelial permeability to lipoprotein influx, is the key pathological event in this experimental model. Subsequent studies in several other animal models have demonstrated either increased 23, 24, 25, 26 or decreased 37 rates of lipoprotein entry into atherosclerosis-susceptible sites, suggesting a nonessential role for alterations in endothelial permeability. All studies agree, however, that prelesional susceptible arterial sites show enhanced retention of apoB-rich, atherogenic lipoproteins. 35, 36, 38, 39, 40, 41 We conclude that alterations in endothelial permeability, though apparently not essential to lesion development, may play a contributory role, eg, in smoking, 42 dyslipidemias 27, 37 (cf Reference 36 36), and possibly hypertension 27 (cf Reference 43 43), but only if some of the infiltrated material is retained. 35 Several other functional modifications have been documented in the endothelial layer in vivo during atherogenesis, but these occur comparatively late. For example, in rabbits, cell adhesion molecules, 44 the earliest known being vascular cell adhesion molecule-1 (VCAM-1), are expressed by endothelial cells that overlie lesions, but only after more than 4 days of severe hypercholesterolemia and resultant foam cell formation. 45 In contrast, lipoprotein retention and aggregation are detectable within minutes to hours after the onset of hypercholesterolemia. 31, 36, 41, 46 Furthermore, atherogenic lipoproteins and their components have been shown to regulate endothelial expression of cell-adhesion molecules. 12, 47, 48, 49 The most straightforward conclusion is that the earliest known endothelial changes during atherogenesis in vivo, such as VCAM-1 expression, cannot be a cause, and are likely to be a consequence, of the initial retention of lipoproteins within the arterial wall (see "Future Directions").

Thiazolidinediones reduce the LDL binding affinity of non-human primate vascular cell proteoglycans

“…Proteoglycans are thought to play a critical role in the development of atherosclerosis, as outlined in the response to retention hypothesis [12]. Proteoglycans are a heterogeneous group of complex molecules, composed of a core protein to which one or more glycosaminoglycan chains are attached [13].…”

Targeting IRE1 with small molecules counteracts progression of atherosclerosis

“…Many metabolic cardiovascular risk factors observed in obesity, including hyperglycemia, hypercholesterolemia, and elevated saturated fats, can induce ER stress in all stages of atherogenesis, the process leading to the development of atherosclerotic plaques. During atherogenesis, a maladaptive inflammatory response is initiated by the deposition of cholesterol-rich lipoproteins in the subendothelial layer of arterial walls (6). Signs of ER stress are most prominent in the atherosclerosis-prone regions of vascular lesions, such as the branching points of arteries, and typically observed in macrophages-among other immune cells-infiltrating these regions (7,8).…”

Dietary Antioxidants Do Not Reduce Fatty Streak Formation in the C57BL/6 Mouse Atherosclerosis Model

“…3 Macrophages do not engulf native LDL quickly enough to form foam cells, 4 but oxidized LDL is recognized by macrophage scavenger receptors, 4,5 leading to fast, unregulated LDL uptake and foam cell formation. 1,3,6 Oxidation of LDL occurs after it has become trapped in the subendothelial matrix because at that site it loses the protection of plasma antioxidants. 6,7 Dietary antioxidants may, however, delay the oxidation of LDL, 8Ϫ11 enabling it to leave the subendothelial space before oxidation occurs.…”

“…1,3,6 Oxidation of LDL occurs after it has become trapped in the subendothelial matrix because at that site it loses the protection of plasma antioxidants. 6,7 Dietary antioxidants may, however, delay the oxidation of LDL, 8Ϫ11 enabling it to leave the subendothelial space before oxidation occurs. 8 This may reduce incorporation of LDL into foam cells and therefore reduce the atheroma development and progression.…”