Recipes for Creating Animal Models of Diabetic Cardiovascular Disease

Hsueh, Willa A.; Abel, E. Dale; Breslow, Jan L.; Maeda, Nobuyo; Davis, Richard C.; Fisher, Edward A.; Dansky, Hayes M.; McClain, Donald A.; McIndoe, Richard A.; Wassef, Momtaz K.; Rabadan‐Diehl, Cristina; Goldberg, Ira J.

doi:10.1161/01.res.0000266449.37396.1f

Cited by 204 publications

(183 citation statements)

References 163 publications

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“…Induction of hyperglycemia in mice. Hyperglycemia was induced in C57/B6 mice (Taconic Hudson NY) using the low-dose streptozotocin (STZ) protocol (15). After a 4-h fast, mice were injected intraperitoneally with either STZ (50 mg/kg) in citrate buffer (pH 4.5) or citrate buffer alone daily for 5 days.…”

Section: Methodsmentioning

confidence: 99%

“…After a 4-h fast, mice were injected intraperitoneally with either STZ (50 mg/kg) in citrate buffer (pH 4.5) or citrate buffer alone daily for 5 days. The protocols used were derived from those published by the Animal Models of Diabetic Complications Consortium, which were developed to allow direct comparison of the studies from a large consortium of multiple investigators (15). Blood glucose measurements.…”

Section: Methodsmentioning

confidence: 99%

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Integrin-Associated Protein Association With Src Homology 2 Domain Containing Tyrosine Phosphatase Substrate 1 Regulates IGF-I Signaling In Vivo

et al. 2008

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OBJECTIVE-Smooth muscle cell (SMC) maintained in medium containing normal levels of glucose do not proliferate in response to IGF-I, whereas cells maintained in medium containing 25 mmol/l glucose can respond. The aim of this study was to determine whether signaling events that have been shown to be required for stimulation of SMC growth were regulated by glucose concentrations in vivo. RESEARCH DESIGN AND METHODS-We compared IGF-Istimulated signaling events and growth in the aortic smooth muscle cells from normal and hyperglycemic mice.RESULTS-We determined that, in mice, hyperglycemia was associated with an increase in formation of the integrin-associated protein (IAP)/Src homology 2 domaine containing tyrosine phosphatase substrate 1 (SHPS-1) complex. There was a corresponding increase in Shc recruitment to SHPS-1 and Shc phosphorylation in response to IGF-I. There was also an increase in mitogen-activated protein kinase activation and SMC proliferation. The increase in IAP association with SHPS-1 in hyperglycemia appeared to be due to the protection of IAP from cleavage that occurred during exposure to normal glucose. In addition, we demonstrated that the protease responsible for IAP cleavage was matrix metalloprotease-2. An anti-IAP antibody that disrupted the IAP-SHPS-1 association resulted in complete inhibition of IGF-I-stimulated proliferation.CONCLUSIONS-Taken together, our results support a model in which hyperglycemia is associated with a reduction in IAP cleavage, thus allowing the formation of the IAP-SHPS-1 signaling complex that is required for IGF-I-stimulated proliferation of SMC.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Integrin-Associated Protein Association With Src Homology 2 Domain Containing Tyrosine Phosphatase Substrate 1 Regulates IGF-I Signaling In Vivo

et al. 2008

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“…Diabetic apoE 2/2 mice develop accelerated renal and vascular injury, with similarities to human diabetic nephropathy and atherosclerosis (24,30). We compared the evolution of diabetes in apoE 2/2 mice after treatment with either vehicle or DMAG at two different concentrations (2 and 4 mg/kg) for 10 weeks.…”

Section: Metabolic and Biochemical Effects Of Hsp90 Inhibitor In Micementioning

confidence: 99%

Targeting HSP90 Ameliorates Nephropathy and Atherosclerosis Through Suppression of NF-κB and STAT Signaling Pathways in Diabetic Mice

et al. 2015

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Heat shock proteins (HSPs) are induced by cellular stress and function as molecular chaperones that regulate protein folding. Diabetes impairs the function/expression of many HSPs, including HSP70 and HSP90, key regulators of pathological mechanisms involved in diabetes complications. Therefore, we investigated whether pharmacological HSP90 inhibition ameliorates diabetes-associated renal damage and atheroprogression in a mouse model of combined hyperglycemia and hyperlipidemia (streptozotocin-induced diabetic apolipoprotein E-deficient mouse). Treatment of diabetic mice with 17-dimethylaminoethylamino-17-demethoxygeldanamycin (DMAG, 2 and 4 mg/kg, 10 weeks) improved renal function, as evidenced by dose-dependent decreases in albuminuria, renal lesions (mesangial expansion, leukocyte infiltration, and fibrosis), and expression of proinflammatory and profibrotic genes. Furthermore, DMAG significantly reduced atherosclerotic lesions and induced a more stable plaque phenotype, characterized by lower content of lipids, leukocytes, and inflammatory markers, and increased collagen and smooth muscle cell content. Mechanistically, the renoprotective and antiatherosclerotic effects of DMAG are mediated by the induction of protective HSP70 along with inactivation of nuclear factor-kB (NF-kB) and signal transducers and activators of transcription (STAT) and target gene expression, both in diabetic mice and in cultured cells under hyperglycemic and proinflammatory conditions. In conclusion, HSP90 inhibition by DMAG restrains the progression of renal and vascular damage in experimental diabetes, with potential implications for the prevention of diabetes complications.

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“…TIF1␣ Ϫ/Ϫ mutants are not hyperglycemic (Table 1 and ref. 24). Their calcifications never affect large arteries, do not have an inflammatory component, and are not associated with lipid deposits, thus excluding atherosclerosis (25).…”

Section: The Calcifying Arteriopathy Of Tif1␣ ؊/؊ Mutant Mice Resemblmentioning

confidence: 99%

Arterial calcifications and increased expression of vitamin D receptor targets in mice lacking TIF1α

Ignat

Teletin

Tisserand

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Calcification of arteries is a major risk factor for cardiovascular mortality in humans. Using genetic approaches, we demonstrate here that the transcriptional intermediary factor 1␣ (TIF1␣), recently shown to function as a tumor suppressor in murine hepatocytes, also participates in a molecular cascade that prevents calcifications in arterioles and medium-sized arteries. We further provide genetic evidence that this function of TIF1␣ is not exerted in hepatocytes. The sites of ectopic calcifications in mutant mice lacking TIF1␣ resemble those seen in mice carrying an activating mutation of the calcium sensor receptor (Casr) gene and, in TIF1␣-deficient kidneys, Casr expression is increased together with that of many other vitamin D receptor (VDR) direct target genes, namely Car2, Cyp24a1, Trpv5, Trpv6, Calb1, S100g, Pthlh, and Spp1. Thus, our data indicate that TIF1␣ represses the VDR pathway in kidney and suggest that an up-regulation of Casr expression in this organ could account for ectopic calcifications generated upon TIF1␣ deficiency. Interestingly, the calcifying arteriopathy of TIF1␣-null mutant mice shares features with the human age-related Mö nckeberg's disease and, overall, the TIF1␣-null mutant pathological phenotype supports the hypothesis that aging is promoted by increased activity of the vitamin D signaling pathway.aging ͉ ectopic calcification ͉ mouse knockout ͉ transcriptional regulation ͉ vitamin D signaling I nitially identified through its ability to interact directly with nuclear receptors in a ligand-dependent manner, transcriptional intermediary factor 1 (TIF1␣), also known as tripartite motif (TRIM24) protein, was subsequently described as both a negative and positive regulator of ligand-induced transactivation acting through chromatin modification (1-6).To address the physiological functions of TIF1␣, we monitored large cohorts of TIF1␣-deficient (TIF1␣ Ϫ/Ϫ ) mice. Hepatic tumors were detected at necropsy in a vast majority of TIF1␣ Ϫ/Ϫ mutants, thus indicating that TIF1␣ deficiency predisposes to liver tumor formation. Tumor predisposition was not observed in TIF1␣ Ϫ/Ϫ mutants heterozygous for the retinoic acid receptor ␣ (Rara) gene, thereby providing genetic proof that TIF1␣ and Rara act in opposition to each other in liver carcinogenesis (6).In the present study, a systematic histological analysis of TIF1␣ Ϫ/Ϫ mutants at different ages was carried out to examine the effect of TIF1␣ gene deletion on a wide range of tissues. This analysis revealed that, aside from occasional metastases from liver tumors (6), TIF1␣ Ϫ/Ϫ mutants displayed calcifications, increasing with age, in extra-hepatic connective tissues, namely arterioles, medium-sized arteries, lungs, and vibrissae. These ectopic calcifications were correlated with an increase in expression of several vitamin D direct targets, therefore raising the possibility that TIF1␣ could repress the vitamin D receptor (VDR) signaling pathway in vivo.

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Recipes for Creating Animal Models of Diabetic Cardiovascular Disease

Cited by 204 publications

References 163 publications

Integrin-Associated Protein Association With Src Homology 2 Domain Containing Tyrosine Phosphatase Substrate 1 Regulates IGF-I Signaling In Vivo

Integrin-Associated Protein Association With Src Homology 2 Domain Containing Tyrosine Phosphatase Substrate 1 Regulates IGF-I Signaling In Vivo

Targeting HSP90 Ameliorates Nephropathy and Atherosclerosis Through Suppression of NF-κB and STAT Signaling Pathways in Diabetic Mice

Arterial calcifications and increased expression of vitamin D receptor targets in mice lacking TIF1α

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