Aortic recruitment of blood lymphocytes is most pronounced in early stages of lesion formation in apolipoprotein-E-deficient mice

Moeller, Flemming; Nielsen, Lars Bo

doi:10.1016/s0021-9150(03)00026-1

Cited by 10 publications

(5 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is well established that classical atherosclerotic lesions have increased expression of ICAM-1 and VCAM-1 compared with nonlesioned arterial wall (22,31,32); we therefore chose to examine aortic gene expression 2 wk after surgery. At this time point, we sought to avoid the biases from differences in lesion extent and at the same time minimized a potential effect of surgical stress on the pattern of gene expression.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

“…The primers for ICAM-1, VCAM-1, and ␤-actin have been described previously (22). The forward and reverse primer sequences for E-selectin were: 5'-ATCTGGTGGCGATTCAGAAC-3', 5'-TGTTGTTTGGTTCACCTGGA-3', and the size of the PCR product was 177 bp.…”

Section: Real-time Pcrmentioning

confidence: 99%

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

View full text Add to dashboard Cite

show abstract

“…Renal failure was induced by a 2-step surgical procedure as previously described 12 . In 8-week old mice, the upper and lower poles of the right kidney were resected leaving an intact kidney segment.…”

Section: Surgical Proceduresmentioning

confidence: 99%

Uremia-Specific Effects in the Arterial Media During Development of Uremic Atherosclerosis in Apolipoprotein E–Deficient Mice

Bro

Borup

Andersen

et al. 2006

ATVB

Self Cite

View full text Add to dashboard Cite

Objective-Uremia accelerates formation of atherosclerosis-like lesions in apolipoprotein E-deficient (apoE Ϫ/Ϫ ) mice. In this study, we compared gene expression patterns in classical and uremic atherosclerosis. Methods and Results-High-density oligonucleotide microarray analyses were performed with aortic RNA from 5/6 nephrectomized (NX) and sham-operated mice. After 12 weeks, NX apoE Ϫ/Ϫ mice had more atherosclerosis and 24 genes were differentially expressed as compared with sham apoE Ϫ/Ϫ mice. Nine genes expressed in muscle cells displayed reduced expression (3.3-to 142-fold, PϽ0.05), whereas osteopontin gene expression was increased 8.7-fold (PϽ0.05) in NX mice. Studies of NX wild-type mice suggested that the changes in NX apoE Ϫ/Ϫ mice were dependent on hypercholesterolemia. Nevertheless, lesioned versus nonlesioned areas of aortas from nonuremic apoE Ϫ/Ϫ mice with classical atherosclerosis displayed less pronounced reductions in expression of the muscle cell related genes than seen in NX apoE Ϫ/Ϫ mice even though the osteopontin gene expression was increased Ϸ15-fold. Electron microscopy showed more vacuolized and necrotic smooth muscle cells within the media underneath both nonlesioned and lesioned intima in NX than in sham apoE Ϫ/Ϫ mice. Conclusion-The results suggest that uremic vasculopathy in apoEϪ/Ϫ mice, in addition to intimal atherosclerosis, is characterized by a uremia-specific medial smooth muscle cell degeneration, which appears to be accentuated by hypercholesterolemia. Key Words: renal failure Ⅲ uremia Ⅲ atherosclerosis Ⅲ vascular smooth muscle cells Ⅲ apolipoprotein E-deficient mice T he cardiovascular mortality rate is increased Ϸ300-fold in 30-year-old individuals on dialysis compared with individuals without renal disease, 1 and even mild renal failure is an independent risk factor of cardiovascular disease. 2,3 Although renal dysfunction often is accompanied by dyslipidemia, hypertension, and diabetes, the high prevalence of cardiovascular disease in patients with renal disease cannot be explained by the classical risk factors alone. 4,5 Thus, renal dysfunction is also associated with nontraditional cardiovascular risk factors, including activation of the renin angiotensin system. 6 Even though renal failure is accompanied by calcification of arteries, 7 it has been controversial whether uremia might accelerate formation of atherosclerosis. Recent experiments from three different groups (including ours) 8 -10 have disclosed that 5/6 nephrectomy (NX) in apolipoprotein E-deficient (apoE Ϫ/Ϫ ) mice accelerates formation of intimal lesions in aorta. NX apoE Ϫ/Ϫ mice develop 6-to 10-times more lesions than sham-operated control mice despite similar blood pressure and plasma homocysteine concentrations, and only minor differences in plasma lipoprotein concentrations. 8,11 The NX mice are also characterized by a low body weight, reduced blood hemoglobin, and increased plasma calcium ϫ phosphate product. 8,11 Intimal lesions in NX mice are qualitatively similar to those in classical atheroscler...

show abstract

“…8 Furthermore, it has been shown that accumulation of lymphocytes within lesions of murine aortas displayed an inverse association with the degree of atherosclerosis. 9 To demonstrate whether the deletion of 2 main chemokine receptors expressed on the principal inflammatory cell types present within atheroma has additional effects on atherogenesis in vivo, we generated double ApoE Ϫ/Ϫ CCR2 Ϫ/Ϫ and ApoE Ϫ/Ϫ CXCR3 Ϫ knockout (KO) mice and ApoE Ϫ/Ϫ CCR2 Ϫ/Ϫ CXCR3 Ϫ triple KO mice. In the present report we describe that the chemokine receptors CCR2 and CXCR3 have differential effects on the development of atherosclerotic lesions.…”

mentioning

confidence: 99%

Differential Influence of Chemokine Receptors CCR2 and CXCR3 in Development of Atherosclerosis In Vivo

Veillard¹,

Steffens²,

Pelli³

et al. 2005

Circulation

128

View full text Add to dashboard Cite

Background-Recruitment of mononuclear leukocytes within atherosclerotic lesions is a critical step in atherogenesis.Mice lacking the chemokine receptor CCR2, highly expressed on macrophages but also on T lymphocytes, show a striking reduction of atherosclerotic lesion formation. The chemokine receptor CXCR3 is a marker of activated T helper type 1 lymphocytes, the principal T lymphocyte type detected within atheroma. We investigated whether the deletion of both of these 2 important receptors expressed on the principal inflammatory cells present in atheroma would further affect atherogenesis in vivo. Methods and Results-We crossed ApoEϪ/Ϫ mice with either CCR2 Ϫ/Ϫ or CXCR3 Ϫ mice and crossed ApoE Ϫ/Ϫ CCR2

show abstract

Aortic recruitment of blood lymphocytes is most pronounced in early stages of lesion formation in apolipoprotein-E-deficient mice

Cited by 10 publications

References 28 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

Uremia-Specific Effects in the Arterial Media During Development of Uremic Atherosclerosis in Apolipoprotein E–Deficient Mice

Differential Influence of Chemokine Receptors CCR2 and CXCR3 in Development of Atherosclerosis In Vivo

Contact Info

Product

Resources

About