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The microtubule associated tumor suppressor gene 1 (MTUS1) is a recently published tumor suppressor gene, which has also been shown to act as an early component in the growth inhibitory signaling cascade of the angiotensin II type 2 receptor (AT2R). In this study we report the generation of MTUS1 knock-out (KO) mice, which develop normally but reveal higher body weights and slightly decreased blood pressure levels. Twenty-eight percent of the studied MTUS1 KO mice also developed heart hypertrophy and 12% developed nephritis, independent of blood pressure levels. Forty-three percent of the MTUS1 KO mice revealed lymphoid hyperplasia affecting spleen (20%), kidney (37%), lung (23%), lymph nodes (17%), and liver (17%) accompanied with leukocytosis, lymphocytosis, and mild anemia. One animal (3%) developed a marginal zone B-cell lymphoma affecting submandibular salivary gland and regional lymph nodes. The symptoms of all mentioned animals are consistent with a B-cell lymphoproliferative disease with features of systemic lupus erythematosus. In addition, body weight of the MTUS1 KO mice was significantly increased and isolated skin fibroblasts showed increased cell proliferation and decreased cell size, compared to wild-type (WT) fibroblasts in response to depleted FCS concentration and lack of growth factors. In conclusion we herein report the first generation of a MTUS1 KO mouse, developing spontaneous heart hypertrophy and increased cell proliferation, confirming once more the anti-proliferative effect of MTUS1, and a SLE-like lymphoproliferative disease suggesting crucial role in regulation of inflammation. These MTUS1 KO mice can therefore serve as a model for further investigations in cardiovascular disease, autoimmune disease and carcinogenesis.

Lp(a) and LDL induce apoptosis in human endothelial cells and in rabbit aorta: Role of oxidative stress. Background Atherogenic lipoproteins cause injury to the vascular wall in the early phase of atherogenesis. We assessed the effects of native (nLDL) and oxidized (oxLDL) low-density lipoprotein (LDL) and lipoprotein (a) [Lp(a)] on O 2 − formation and cell death in cultured human umbilical vein endothelial cells (HUVECs) and rabbit aorta (RA). Methods and Results O 2 − formation of HUVECs and RA segments was not influenced by nLDL, but was dose dependently increased by oxLDL and was moderately increased by nLp(a). oxLp(a) was the most potent stimulus for O 2 − formation, increasing it in HUVECs by 356% at 5 μg/ml and in RA by 294% at 100 μg/ml. Apoptosis was detected by DNA fragmentation and Annexin assay in HUVECs and by TUNEL staining in RA. Incubation of HUVECs and RA with oxLDL, but not nLDL, dose and time dependently induced apoptosis with only a minimal effect on necrosis. nLp(a) elicited a small but significant effect on apoptosis, whereas oxLp(a) induced apoptosis more potently than oxLDL in HUVECs and RA and caused necrotic cell death in HUVECs. Induction of apoptosis by oxLDL and oxLp(a) in RA was enhanced by the superoxide dismutase (SOD) inhibitor, diethyl-dithio-carbamate, and was blunted by SOD and catalase in HUVECs and RA, suggesting that O 2 − formation was involved. The concentration of lysophosphatidylcholine, a lipoprotein oxidation product and stimulus for O 2 − formation, was significantly enhanced by factor 5 in oxLDL and by factor 7 in oxLp(a) compared with native lipoproteins. Conclusion Atherogenic lipoproteins stimulate O 2 − formation and induction of apoptosis in HUVECs and RA, and may thereby influence the pathogenesis of atherosclerosis.

We assessed effects of reactive oxygen metabolites on renin release of juxtaglomerular cells (JG-cells) prepared in primary culture from mouse kidneys. Renin activity was measured in culture supernatants and cells. Basal renin release was increased by incubation of JG-cells with xanthine/xanthine oxidase from 26 ± 1% up to 58 ± 3% of total activity. This increase was slightly inhibited by superoxide dismutase, and was eliminated by addition of catalase, implicating H2O2 as an intermediate product in the stimulatory cascade. H2O2 applied exogeneously dose-dependently stimulated renin release up to 55 ± 2%; this effect was also prevented by catalase. We propose that reactive oxygen metabolites stimulate renin release in isolated JG-cells. This could have important implications in inflammatory kidney diseases.