Coronary plaques in patients with end-stage renal failure are characterized by increased media thickness and marked calcification. In contrast to the previous opinion the most marked difference compared to non-uraemic controls does not concern the size, but the composition of the plaque. Deposition of calcium within the plaques may contribute to the high complication rate in uraemic patients.

Abstract. Rodents do not develop spontaneous atherosclerosis. Currently, there is no good animal model to study the effect of uremia on atherosclerosis. This study evaluated whether apolipoprotein E knockout (ApoeϪ/Ϫ) mice are useful to study the effect of renal dysfunction on cardiovascular risk. ApoeϪ/Ϫ mice have decreased serum apolipoprotein E and exhibit lipid abnormalities and atherosclerosis even on a lowcholesterol diet. Ten-wk-old ApoeϪ/Ϫ mice were subtotally nephrectomised (SNX ApoeϪ/Ϫ; n ϭ 8), uninephrectomised (UNX ApoeϪ/Ϫ; n ϭ 5), or sham-operated (sham ApoeϪ/Ϫ; n ϭ 5) and compared with their genetic controls (SNX C57/ BL6; UNX C57/BL6; sham C57/BL6). After 12 wk, BP was measured intraarterially, blood samples were taken, and the experiment was terminated by perfusion fixation. The heart weight was determined, and quantitative morphologic analysis of intramyocardial arteries and aortic changes was performed. At the end of the experiment, heart weight and relative left ventricular weight were comparable in all groups. Intraarterial BP was somewhat higher in ApoeϪ/Ϫ mice compared with controls. Baseline serum cholesterol and triglyceride levels were higher in ApoeϪ/Ϫ mice than in C57/BL6. Atherosclerotic plaques were not present in sham or UNX C57/BL6, but minor plaque formation was noted in some SNX control animals. In contrast, beginning plaques were seen even in untouched ApoeϪ/Ϫ mice, and strikingly increased plaque formation was noted in UNX and SNX ApoeϪ/Ϫ mice. Maximal plaque diameter (cross-section) was 37 Ϯ 74 m in SNX C57/BL6, 191 Ϯ 90 m in sham ApoeϪ/Ϫ, 323 Ϯ 66 m in UNX ApoeϪ/Ϫ, and 457 Ϯ 17 m in SNX ApoeϪ/Ϫ. The plaque morphology corresponded with that of early plaques characterized by foam cells and virtual absence of lymphocytes or smooth muscle cell infiltration. In conclusion, even mild renal dysfunction, i.e., after uninephrectomy, causes a dramatic increase in plaque size and aggressive morphology (foam cell rich soft plaques) in the animal model of the ApoeϪ/Ϫ mouse.After the seminal communication of Lindner et al. (1), the high prevalence and possibly accelerated development of atherosclerosis have been well documented in patients with renal failure. Because of the multitude of classical and non-classical atherosclerosis risk factors, e.g., hypertension, dyslipidemia, hyperhomocysteinemia, increased oxidative stress, it has remained controversial whether the high burden of atherosclerosis in uremia can be explained by classical risk factors or whether uremia per se aggravates or accelerates atherosclerosis.With the exception of diabetic patients with renal failure (2), there has been little documentation that atherosclerotic complications evolve more rapidly in patients with renal failure, and it has generally been difficult to reproduce atherosclerosis in animal models of renal failure.The apolipoprotein E knockout mouse (ApoeϪ/Ϫ) is a wellestablished model to study atherogenesis (3,4). We reasoned that it might also constitute a suitable model to address the issue whether athero...

Microsatellite instability (MSI) occurs in most hereditary nonpolyposis colorectal cancers (HNPCC) and less frequently in sporadic tumors as the result of DNA mismatch repair (MMR) deficiency. Instability at coding microsatellites (cMS) in specific target genes causes frameshift mutations and functional inactivation of affected proteins, thereby providing a selective growth advantage to MMR deficient cells. At present, little is known about Selective Target Gene frameshift mutations in preneoplastic lesions. In this study, we examined 30 HNPCC-associated MSI-H colorectal adenomas of different grades of dysplasia for frameshift mutations in 26 cMS-bearing genes, which, according to our previous model, represent Selective Target genes of MSI. About 30% (8/26) of these genes showed a high mutation frequency (X50%) in colorectal adenomas, similar to the frequencies reported for colorectal carcinomas. Mutations in one gene (PTHL3) occurred significantly less frequently in MSI adenomas compared to published mutation rates in MSI carcinomas (36.0 vs 85.7%, P ¼ 0.023). Biallelic inactivation was observed in nine genes, thus emphasizing the functional impact of cMS instability on MSI tumorigenesis. Some genes showed a high frequency of frameshift mutations already at early stages of MSI colorectal tumorigenesis that increased with grade of dysplasia and transition to carcinoma. These include known Target Genes like BAX and TGFBR2, as well as three novel candidates, MACS, NDUFC2, and TAF1B. Overall, we have identified genes of potential relevance for the initiation and progression of MSI tumorigenesis, thus representing promising candidates for novel diagnostic and therapeutic approaches directed towards MMRdeficient tumors.

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Treatment with the antioxidant dl-alpha-tocopherol prevented cardiomyocyte/capillary mismatch, and to some extent also myocardial fibrosis in rats with renal failure. The results point to a role of oxidative stress in the genesis of myocardial interstitial fibrosis and capillary deficit of the heart.

These findings illustrate that bradykinin plays an important role for the beneficial effect of Ramipril in preventing (and potentially reversing) abnormal cardiovascular structure in uremic hypertensive rats.

Despite some glomerulosclerosis and elevated mean arterial blood pressure at baseline, no acceleration of progression of renal disease was found in this genetic model of hyperlipoproteinaemia. This observation suggests that despite the known spontaneous histological changes in untouched kidneys, however, the presence of hyperlipidaemia in the ApoE(-/-) mouse does not cause more severe progression in the present models of moderate renal disease.

Left ventricular hypertrophy (LVH) develops very early in experimental renovascular hypertension after clipping of one renal artery and is accompanied by a remodeling of cardiac structure which has not yet been investigated in detail. It was the aim of the present study to analyze changes in cardiomyocyte number and volume in LVH after 2 weeks of renovascular hypertension. Sprague-Dawley rats were subjected to clipping of the left renal artery (2K1C) or sham operation (sham). One group of 2K1C rats received antihypertensive treatment with dihydralazine. The experiment was terminated after 2 weeks. Hearts were investigated using stereological methods, electron microscopy, immunohistology for the proliferation marker proliferating cell nuclear antigen, the pro-and anti-apoptotic proteins Bax and Bcl-2 as well as the TUNEL technique. After 2 weeks, systolic blood pressure and relative left ventricular weight were significantly higher in untreated 2K1C animals than in sham and dihydralazine-treated 2K1C rats. Volume fraction of interstitial tissue and capillary length density were not different, whereas wall thickness of intramyocardial arteries was significantly higher in untreated 2K1C (5.12€0.7 m) than in sham (3.92€0.6 m) and in dihydralazine-treated 2K1C (3.91€0.7 m) rats. Cardiomyocyte diameter and volume were significantly higher in untreated 2K1C than in sham animals. The number of cardiomyocytes per left ventricle was significantly lower in untreated 2K1C rats (5.5€1.6 vs 3.9€6.9 10 7 ). Using immunohistochemistry, no direct evidence of apoptosis was found, but a relative higher expression of the anti-apoptotic protein bcl-2 expression was seen in untreated 2K1C than in sham animals. This may reflect a protective mechanism as a consequence of earlier occurring apoptosis. These observations document that experimental renovascular hypertension induces a rapidly developing LVH characterized by marked cardiac remodeling and substantial loss of cadiomyocytes.