Uremia Accelerates both Atherosclerosis and Arterial Calcification in Apolipoprotein E Knockout Mice

Abstract

Chronic renal failure (CRF) favors the development of atherosclerosis and excessive calcification of atheromatous lesions. CRF was induced in apolipoprotein E knockout (apoE ؊/؊ ) mice to study (1) a possible acceleration of aortic atherosclerosis, (2) the degree and type of vascular calcification, and (3) factors involved in the calcification process. For creating CRF, 8-wk-old apolipoprotein E gene knockout (apoE ؊/؊ ) mice underwent partial kidney ablation. Control animals underwent sham operation. Aortic atherosclerotic plaques and calcification were evaluated using quantitative morphologic image processing. At 6 wk after nephrectomy, CRF mice had significantly higher serum urea, cholesterol, and triglyceride concentrations than non-CRF controls. The serum levels of advanced oxidation protein products were elevated in the uremic group and were correlated with serum urea levels. Atherosclerotic lesions in thoracic aorta were significantly larger in uremic apoE ؊/؊ mice than in nonuremic controls. The relative proportion of calcified area to total surface area of both atherosclerotic lesions and lesion-free vascular tissue was increased in aortic root of uremic apoE ؊/؊ mice when compared with controls. The calcium deposits were made of hydroxyapatite and calcite crystals. In addition, plaques from uremic animals showed a significant increase in collagen content, whereas the degree of macrophage infiltration was comparable in both groups. There was no difference in mean arterial BP. These findings demonstrate that CRF aggravates atherosclerosis in apoE ؊/؊ mice. Moreover, CRF enhances arterial calcification at both atheromatous intimal sites and atheroma-free medial sites. We anticipate that this experimental model will be useful to test treatment strategies aimed at decreasing the accelerated atherosclerosis and arterial calcification in uremia

Myeloperoxidase-derived oxidants damage artery wall proteins in an animal model of chronic kidney disease–accelerated atherosclerosis

“…Similar to our findings, Massy et al discovered that the relative proportion of atherosclerotic lesions to lesion-free vascular tissue is increased in the aortic root of uremic apoE -/-mice when compared with controls (96). Our model did not show any changes in serum calcium and phosphate levels but did indicate increased iPTH.…”

“…Plaque composition in uremic apoE -/-mice demonstrates macrophage infiltration, increased cholesterol, collagen, and calcium content than classical atherosclerosis (96). Although we did not observe more than minimal changes in serum calcium and phosphate, this model and the apoE -/-model nonetheless exhibit significantly increased vascular calcification demonstrated in prior work by other groups (59,60,(96)(97)(98)(99).In conclusion, our study demonstrates for the first time that increased MPO levels and activity co-localizes with lesional macrophages in the artery wall in a mouse model of CKD-atherosclerosis. In addition to decreased cholinergic response in the vessel, our work suggests that MPO expression and activity may play an important role in the propagation of atherosclerotic lesions in CKD mice.…”

“…Plaque composition in uremic apoE -/-mice demonstrates macrophage infiltration, increased cholesterol, collagen, and calcium content than classical atherosclerosis (96). Although we did not observe more than minimal changes in serum calcium and phosphate, this model and the apoE -/-model nonetheless exhibit significantly increased vascular calcification demonstrated in prior work by other groups (59,60,(96)(97)(98)(99).…”

T Cell CX3CR1 Mediates Excess Atherosclerotic Inflammation in Renal Impairment

“…4,5 Already this moderate decrease in renal function increases atherosclerotic lesion size paralleling the increase in atherosclerotic lesion burden observed in humans. 4,6,7 These atherosclerotic mouse strains have been employed for the investigation of mechanisms of increase in atherosclerosis in moderate renal impairment. 5,7,8 Inflammatory leukocytes promote growth and regulate composition and thereby stability of the atherosclerotic plaque.…”

“…4,6,7 These atherosclerotic mouse strains have been employed for the investigation of mechanisms of increase in atherosclerosis in moderate renal impairment. 5,7,8 Inflammatory leukocytes promote growth and regulate composition and thereby stability of the atherosclerotic plaque. [9][10][11] T cells are major modifiers of plaque formation among adaptive immune cells.…”