A physiologically relevant atherogenic diet causes severe endothelial dysfunction within 4 weeks in rabbit

Abstract

A physiological atherogenic human diet consists of 0.1% cholesterol, fat, as well as high levels of methionine, which is the precursor to homocysteine. The pathological effects of a diet enriched with physiologically high levels of cholesterol, methionine and fat over a short period on the aorta are unknown. In this regard, we sought to determine the effects of a 0.1% cholesterol diet in combination with a 1% methionine over a 4-week period on endothelial function and artery pathology and the expression of endothelial nitric oxide synthase as well as nitrosative stress by nitrotyrosine (NT), oxidative stress by heat shock protein 70 (HSP70) and endoplasmic reticulum stress by glucose regulated protein 78 (GRP78). Rabbits were fed for 4 weeks a diet supplemented with 1% methionine + 0.1% cholesterol + 5% peanut oil (MC). The endothelial function of the abdominal aorta was examined using organ bath techniques, atherosclerosis determined in each artery by microscopy and eNOS, NT, GRP78 and HSP70 by standard immunohistochemistry. Endothelium dependent relaxation in response to acetylcholine significantly decreased by 63% at 1 muM acetylcholine (P < 0.001) compared with control arteries. There was no evidence of atherosclerosis formation in any artery studied, however, eNOS, NT and GRP78 was clearly present in all arteries studied but HSP70 was not easily detectable. Severe endothelial dysfunction is present in the abdominal aorta of rabbits within 4 weeks of physiological dietary manipulation, possibly due to NT formation and endoplasmic reticulum stress. This model could be used to study the early onset of endothelial dysfunction prior to the initiation of atherosclerosis.

Role of Peptide YY in blood vessel function and atherosclerosis in a rabbit model

“…This led to an increase in maximal constriction in this group. This effect could be due to reduced basal NO bioavailability, as this diet has been previously shown in this laboratory to induce severe reduction in NO bioavailability …”

Alamandine reverses hyperhomocysteinemia‐induced vascular dysfunction via PKA‐dependent mechanisms

“…However, PDE inhibitors unfortunately inhibit cyclic GMP activating PKG, thus limiting their use in determining the precise activation of PKA, which can confound the results. We propose that as HHcy is reported to increase the peroxynitrate milieu and peroxynitrate upregulates PKA in cardiac homogenates, a peroxynitrate donor, such as SIN‐1, could be used to restore the effects of PKA inhibition. Further studies are required to establish this hypothesis.…”

Plasma and Aorta Biochemistry and MMPs Activities in Female Rabbit Fed Methionine Enriched Diet and Their Offspring

“…Rai et al [1] demonstrated that Hcy caused ER stress and thus UPR (unfolded protein response) because it raised the GRP 78 (glucose-regulated protein), a molecular chaperone involved in the UPR.…”

“…Miller et al [72] mentioned reduction of NO rate in both endothelial and platelet levels. The endothelial dysfunction appears to be due to nitrosative and endoplasmic reticulum stress rather than oxidative stress or lack of eNOS [1]. Kruzliak et al [73] showed that oxidized LDL induces ER stress via a LOX-1 pathway, with other stress pathways leading to endothelial dysfunction.…”

“…Met enriched diet causes hyperhomocysteinemia (Hhcy), which is associated with the metabolic syndrome, oxidative and nitrosative endoplasmic reticulum stress [1], inflammation, unfolded protein response, cell death, and increased cardiovascular risk [2]. …”