Chronic Renal Failure Accelerates Atherogenesis in Apolipoprotein E–Deficient Mice

Bro, Susanne; Bentzon, Jacob Fog; Falk, Erling; Andersen, Claus B.; Ølgaard, Klaus; Nielsen, Lars Bo

doi:10.1097/01.asn.0000088024.72216.2e

Cited by 139 publications

(152 citation statements)

References 52 publications

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“…Thus both the morphologic and biochemical analyses in this study suggest that accelerated initiation and expansion of lesions rather than specific lesion composition is the key characteristic of early uremic atherosclerosis in apo-EϪ/Ϫ mice. This notion is in accordance with our former study, where we studied mice that had been uremic for 22 wk and had extensive aortic atherosclerosis with a mean total plaque area of 0.27 (8). In that study, we observed aortic lesions with extracellular lipids, lipid-filled macrophages, lymphocytes, and collagen-rich connective tissue, i.e.…”

Section: Discussionsupporting

confidence: 92%

“…characteristics of more advanced classical atherosclerosis. Remarkably, aortic calcifications are virtually absent in uremic apo-EϪ/Ϫ mice (8,9), despite significantly elevated plasma concentrations of calcium and phosphate (8). As previously discussed (8), the explanation for the elevated plasma calcium concentration in uremic mice and dogs (30) remains enigmatic.…”

Section: Discussionmentioning

confidence: 92%

“…The uremic lesions are characterized by marked accumulation of macrophages, nitrotyrosine (a marker of reactive oxygen species-protein interaction) (8,9), and highlevel expression of receptors for advanced glycation end products (RAGE) (9). Remarkably, the accelerated lesion formation in the uremic mice cannot be fully explained by risk factors that are normally believed to cause vascular disease in uremic patients (e.g., changes in plasma lipoproteins, BP, and plasma homocysteine) (8). This finding is in line with a recent clinical study that showed a disappointingly small effect on cardiovascular disease in uremic patients by treatment with a cholesterol-lowering statin (11).…”

mentioning

confidence: 99%

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Increased Expression of Adhesion Molecules in Uremic Atherosclerosis in Apolipoprotein-E–Deficient Mice

Bro¹,

Moeller²,

Andersen

et al. 2004

Journal of the American Society of Nephrology

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Abstract. Chronic renal failure markedly accelerates atherosclerosis in apolipoprotein-E-deficient mice, but the mechanism is unknown. The recruitment of inflammatory cells in the arterial wall by vascular adhesion molecules plays a key role in the formation of classical atherosclerosis. This study examines whether the expression of vascular adhesion molecules is increased in uremic atherosclerosis. Uremia was induced by 5/6 nephrectomy; control mice were sham-operated. After 2 wk of uremia, no lesion formation could be demonstrated in uremic or control mice. After 12 wk, aortas from uremic mice had a 9.8-fold increase of the aortic plaque area fraction compared with control mice (P Ͻ 0.0001). The aortic expression of intercellular adhesion molecule-1 (ICAM-1) mRNA in uremic mice was 215 Ϯ 31% (P Ͻ 0.05) and 243 Ϯ 55% (P Ͻ 0.05) of that in controls after 2 and 12 wk, respectively (n ϭ 9 ϫ 4). In contrast, aortic expression of vascular cell adhesion molecule-1 (VCAM-1) mRNA in uremic mice was unchanged after 2 wk but increased to 237 Ϯ 40% (P Ͻ 0.01) of that in control mice after 12 wk. On immunohistochemistry of aortas from uremic mice, ICAM-1 was predominantly present in endothelial cells both in nonlesioned and lesioned aortas, whereas VCAM-1 was predominantly present in the medial smooth muscle cell layer in lesioned aortas. The plasma concentration of soluble ICAM-1 (sICAM-1) (but not of sVCAM-1) was slightly elevated after 2 wk of uremia. In contrast, both sICAM-1 and sVCAM-1 plasma concentrations were markedly higher in uremic than control mice after 12 wk. These results suggest that uremic atherosclerosis is preceded by an upregulation of ICAM-1 expression in arterial endothelium and that formation of early uremic lesions is accompanied by upregulation of VCAM-1 expression in the medial smooth muscle cell layer.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 92%

mentioning

confidence: 99%

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Increased Expression of Adhesion Molecules in Uremic Atherosclerosis in Apolipoprotein-E–Deficient Mice

Bro¹,

Moeller²,

Andersen

et al. 2004

Journal of the American Society of Nephrology

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“…In a study by Bro et al, uremic apoE -/-mice that were fed a regular diet for 22 weeks had 50% higher total plasma cholesterol concentrations than normal apoE -/-mice (94). Plasma triglyceride concentrations did not differ between uremic and normal apoE -/-mice (94,95). This is in contrast to our trend of decreased cholesterol and triglycerides in CKD LDLr -/-mice when compared to CTL mice regardless of diet.…”

Section: Discussioncontrasting

confidence: 80%

“…Our model of CKD atherosclerosis is the first of its kind to demonstrate marked upregulation of mouse MPO and its specific oxidation products in response to reduced renal function and HFD in murine atherosclerosis. Similar to our work, apolipoprotein E deficient (apoE -/-) mice with chronic renal failure demonstrate enhanced atherosclerosis with increased macrophage infiltration and 3-nitrotyrosine expression in their atherosclerotic lesions, suggesting a similar process is plausible (81). However, this study did not specifically investigate if MPO or MPO-specific oxidation products are elevated.…”

Section: Discussionmentioning

confidence: 55%

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

Zeng

Mathew

Byun

et al. 2018

Journal of Biological Chemistry

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Increased myeloperoxidase (MPO) levels and activity are associated with increased cardiovascular risk among individuals with chronic kidney disease (CKD). However, a lack of good animal models for examining the presence and catalytic activity of MPO in vascular lesions has impeded mechanistic studies into CKD-associated cardiovascular diseases. Here, we show for the first time that exaggerated atherosclerosis in a pathophysiologically relevant CKD mouse model is associated with increased macrophage-derived MPO activity. Male 7-week-old LDL receptordeficient mice underwent sham (control mice) or 5/6 nephrectomy and were fed either a low-fat or high-fat, high-cholesterol diet for 24 weeks, and the extents of atherosclerosis and vascular reactivity were assessed. MPO expression and oxidation products, and the protein-bound oxidized tyrosine moieties 3-chlorotyrosine, 3-nitrotyrosine, and o,o′-dityrosine were examined with immunoassays and confirmed with mass spectrometry (MS). As anticipated, the CKD mice had significantly higher plasma creatinine, urea nitrogen, and intact parathyroid hormone along with lower hematocrit and body weight. On both the diet regimens, CKD mice did not have hypertension but had lower cholesterol and triglyceride levels than the control mice. Despite the lower cholesterol levels, CKD mice had increased aortic plaque areas, fibrosis, and luminal narrowing. They also exhibited increased MPO expression and activity (i.e., increased oxidized tyrosines) that co-localized with infiltrating lesional macrophages and diminished vascular reactivity. In summary, unlike non-CKD mouse models of atherosclerosis, CKD mice exhibit increased MPO expression and catalytic activity in atherosclerotic lesions, which colocalize with lesional macrophages. These results implicate macrophage-derived MPO in CKDaccelerated atherosclerosis.Chronic kidney disease (CKD) affects 15% of Americans, and cardiovascular disease (CVD) continues to be the leading cause of mortality in Myeloperoxidase oxidizes artery proteins in kidney disease2 these patients (>10-fold mortality compared to the general population) (1-6). An increased risk for CVD is evident even in milder and non-albuminuric forms of CKD and cannot be fully explained by traditional risk factors (7-10). Furthermore, control of established risk factors such as hyperlipidemia results in substantially lower risk reduction in CKD patients compared to the general population (11). Recent evidence supports the key role of nontraditional risk factors (e.g., oxidative stress) in the pathogenesis of CVD in CKD (12-17), suggesting that CKD-specific mechanisms are responsible for CVD in kidney patients.Atherosclerosis, the major cause of CVD, is a chronic inflammatory disease characterized by the infiltration of lipids and inflammatory cells, such as monocyte-derived macrophages and Tlymphocytes, into the artery wall (18). While elevated levels of low-density lipoprotein (LDL) are known to increase the risk of atherosclerosis greatly (19), in vitro studies sugges...

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Mitochondrial Damage‐Induced Innate Immune Activation in Vascular Smooth Muscle Cells Promotes Chronic Kidney Disease‐Associated Plaque Vulnerability

Wang

et al. 2021

Advanced Science

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Chronic kidney disease (CKD) is associated with accelerated atherosclerosis progression and high incidence of cardiovascular events, hinting that atherosclerotic plaques in CKD may be vulnerable. However, its cause and mechanism remain obscure. Here, it is shown that apolipoprotein E‐deficient (ApoE−/−) mouse with CKD (CKD/ApoE−/− mouse) is a useful model for investigating the pathogenesis of plaque vulnerability, and premature senescence and phenotypic switching of vascular smooth muscle cells (VSMCs) contributes to CKD‐associated plaque vulnerability. Subsequently, VSMC phenotypes in patients with CKD and CKD/ApoE−/− mice are comprehensively investigated. Using multi‐omics analysis and targeted and VSMC‐specific gene knockout mice, VSMCs are identified as both type‐I‐interferon (IFN‐I)‐responsive and IFN‐I‐productive cells. Mechanistically, mitochondrial damage resulting from CKD‐induced oxidative stress primes the cyclic GMP‐AMP synthase‐stimulator of interferon genes (cGAS‐STING) pathway to trigger IFN‐I response in VSMCs. Enhanced IFN‐I response then induces VSMC premature senescence and phenotypic switching in an autocrine/paracrine manner, resulting in the loss of fibrous cap VSMCs and fibrous cap thinning. Conversely, blocking IFN‐I response remarkably attenuates CKD‐associated plaque vulnerability. These findings reveal that IFN‐I response in VSMCs through immune sensing of mitochondrial damage is essential for the pathogenesis of CKD‐associated plaque vulnerability. Mitigating IFN‐I response may hold promise for the treatment of CKD‐associated cardiovascular diseases.

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Chronic Renal Failure Accelerates Atherogenesis in Apolipoprotein E–Deficient Mice

Cited by 139 publications

References 52 publications

Increased Expression of Adhesion Molecules in Uremic Atherosclerosis in Apolipoprotein-E–Deficient Mice

Increased Expression of Adhesion Molecules in Uremic Atherosclerosis in Apolipoprotein-E–Deficient Mice

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

Mitochondrial Damage‐Induced Innate Immune Activation in Vascular Smooth Muscle Cells Promotes Chronic Kidney Disease‐Associated Plaque Vulnerability

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