The Injury InflammationIschemia Hypothesis of Atherosclerosis

Injury-inflammation-ischemia hypothesis of atherosclerosis

Adapted from Okuyama et al. [2000].

Injury-inflammation-ischemia hypothesis of atherosclerosis

Adapted from Okuyama et al. [2000].

Chlamydia, herpes virus and other pathogens are presumed to injure blood vessels [Ross, 1999]. Postprandial hypertriglyceridemia is also proposed to trigger the vessel injury (fig. 75, 76). Advanced glycation endproducts (AGE) may also trigger endothelial injury (fig. 81). Inflammatory reactions would follow to repair the injury. When LA intake is high and membrane phospholipids are saturated with AA, the enhanced LA cascade leads to persistent inflammation by over- and unbalanced production of eicosanoids (elevated TXA2/PGI2 ratio and increased leukotriene production). Increased thrombotic tendency leads to ischemia and inflammation. Reactive oxygen species produced by hypoxic (ischemic) mitochondria and/or inflammatory cells attack LDL to form oxidized LDL, stimulate cell-proliferation and thereby accelerate atherogenesis. The lipid factor I in this figure is associated with «6/«3 balance and the LA cascade.

On the other hand, cholesterol synthesis mediated through SREBPs is stimulated by FAs; the stimulatory activity appears to be roughly in the order of S, M 6 LA > ALA > EPA, DHA (AA), an interpretation from experiments using cultured cells and animals (Lipid Factor II). At this step, relatively little difference is observed neither between animal fat (S, M) and high-LA vegetable oils, nor between «6 and «3 FAs. Thus, S and M, and LA to a slightly lesser extent, possibly elevate the levels of isoprenyl intermediates, suppress the formation of vasodilatory NO, promote cell proliferation through prenylation of oncogene products (Ras, Rho) and accelerate atherogenesis. High levels of TC and oxidized cholesterol feedback suppress cholesterol synthesis. Thus, «3 FAs, especially EPA and DHA, suppress atherogenesis by competitively inhibiting the LA cascade (lipid factor I), by suppressing cholesterol synthesis (prenyl intermediate levels) and by promoting P-oxidation and thermogenesis (lipid factor II), all involving altered gene expressions.

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