Anti-inflammatory effects of atorvastatin improve left ventricular function in experimental diabetic cardiomyopathy

Linthout, Sophie Van; Riad, Alexander; Dhayat, Nasser; Spillmann, Frank; Du, Jing; Dhayat, Sameer; Westermann, Dirk; Hilfiker‐Kleiner, Denise; Noutsias, Michel; Laufs, Ulrich; Schultheiss, Heinz‐Peter; Tschöpe, Carsten

doi:10.1007/s00125-007-0719-8

Cited by 118 publications

(94 citation statements)

References 43 publications

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“…23 The STZ-induced diabetes mellitus model is characterized by severe HG and is, in contrast to other diabetic animal models, not associated with reduced HDL levels. 24,25 Apo A-I gene transfer did not affect glucose or LDL cholesterol levels, 2 factors known to influence AT1R expression and reduced aortic AT1R mRNA in STZ-induced diabetic rats to levels similar to nondiabetic controls. In addition, a dose-dependent effect of HDL in attenuating HG-induced elevated AT1R expression was observed.…”

Section: Discussionmentioning

confidence: 87%

Vascular-Protective Effects of High-Density Lipoprotein Include the Downregulation of the Angiotensin II Type 1 Receptor

et al. 2009

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Abstract-There is growing evidence that a cross-talk exists between the renin-angiotensin (Ang) system and lipoproteins.We investigated the role of high-density lipoprotein (HDL) on Ang II type 1 receptor (AT1R) regulation and subsequent Ang II-mediated signaling under diabetic conditions. To investigate the effect of HDL on AT1R expression in vivo, apolipoprotein A-I gene transfer was performed 5 days after streptozotocin injection. Six weeks after apolipoprotein A-I gene transfer, the 1.9-fold (Pϭ0.001) increase of HDL cholesterol was associated with a 4.7-fold (PϽ0.05) reduction in diabetes mellitus-induced aortic AT1R expression. Concomitantly, NAD(P)H oxidase activity, Nox 4, and p22 phox mRNA expression were reduced 2.6-fold, 2.0-fold, and 1.5-fold (PϽ0.05), respectively, whereas endothelial NO synthase dimerization was increased 3.3-fold (PϽ0.005). Apolipoprotein A-I transfer improved NO bioavailability as indicated by ameliorated acetylcholine-dependent vasodilation in the streptozotocin-Ad.hapoA-I group compared with streptozotocin-induced diabetes mellitus. In vitro, HDL reduced the hyperglycemia-induced upregulation of the AT1R in human aortic endothelial cells. This was associated with a 1.3-fold and 2.2-fold decreases in reactive oxygen species and NAD(P)H oxidase activity, respectively (PϽ0.05). Finally, HDL reduced the responsiveness to Ang II, as indicated by decreased oxidative stress in the hyperglycemiaϩHDLϩAng II group compared with the hyperglycemiaϩAng II group. In conclusion, vascular-protective effects of HDL include the downregulation of the AT1R. Diabetes mellitus is associated with endothelial dysfunction, an early phase of atherosclerosis further characterized by a reduction in NO bioavailability, without significant morphological changes of the vessel wall. 1,2 Both diabetes mellitus-associated hyperglycemia and increased angiotensin (Ang) II levels 3 induce reactive oxygen species (ROS), which contribute to endothelial dysfunction, partly via oxidative degradation of NO. Recent studies have demonstrated that ROS are predominantly produced by vascular NAD(P)H oxidase (NOX), 4 whereas "uncoupled" endothelial NO synthase (eNOS; when eNOS produces O 2 ⅐Ϫ rather then NO) is another important source of ROS in diseased, including diabetic, blood vessels. 5 Numerous studies have shown that activation of the Ang II type 1 receptor (AT1R) contributes to the induction of oxidative stress and apoptosis of vascular cells, thus contributing to the initiation and progression of endothelial dysfunction. 6 Ang II not only increases NOX activity but also uncouples eNOS in diabetic mice. 7 The expression levels of the AT1R define the biological efficacy of Ang II and have been shown to be regulated by several agonists, such as Ang II, glucose, insulin, ROS, low-density lipoprotein (LDL), and many others, 8,9 including diabetes mellitus. 10,11 The importance of the enhanced vascular AT1R expression and Ang II-mediated signaling in diabetes mellitus-associated endothelial dysfunction follows from the ...

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Section: Discussionmentioning

confidence: 87%

Vascular-Protective Effects of High-Density Lipoprotein Include the Downregulation of the Angiotensin II Type 1 Receptor

et al. 2009

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“…HDLs have antidiabetic features (dotted lines): they reduce hyperglycaemia and dyslipidaemia via-among other mechanisms-their capacity to decrease pancreatic β-cell apoptosis and adipocyte lipolysis, respectively, and they increase insulin sensitivity via the induction of adiponectin, abrogating the development of hyperinsulinaemia. Besides interference with the triggers that lead to diabetic cardiomyopathy, HDLs reduce the features of diabetic cardiomyopathy via their pleiotropic effects, including their anti-oxidative, antifibrotic, anti-inflammatory, antiapoptotic, and endothelial-protective effects ( full lines) hypothesis has been evaluated in an experimental rat model of streptozotocininduced diabetes mellitus associated with severe hyperglycaemia and an LDL to HDL ratio of 1:1 (Van Linthout et al 2007;Young et al 1988). …”

Section: Human Apo A-i Gene Transfer Attenuates Diabetic Cardiomyopathymentioning

confidence: 99%

Therapeutic Potential of HDL in Cardioprotection and Tissue Repair

Linthout

Frias²,

Singh

et al. 2014

High Density Lipoproteins

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“…Animal experiments were carried out according to the regulations of the local Animal Care and Use Committee. Animals were made diabetic by a single intraperitoneal injection of 55 mg/kg of streptozotocin (Sigma, St Louis, IL, USA) in 100 mmol/l sodium citrate (pH 4.5) [45]. Control animals were injected with vehicle only.…”

Section: Methodsmentioning

confidence: 99%

Glucose increases hepatic lipase expression in HepG2 liver cells through upregulation of upstream stimulatory factors 1 and 2

Deursen¹,

Jansen²,

Verhoeven³

2008

Diabetologia

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Aims/hypothesis Elevated hepatic lipase (HL, also known as LIPC) expression is a key factor in the development of the atherogenic lipid profile in type 2 diabetes and insulin resistance. Recently, genetic screens revealed a possible association of type 2 diabetes and familial combined hyperlipidaemia with the USF1 gene. Therefore, we investigated the role of upstream stimulatory factors (USFs) in the regulation of HL. Methods Levels of USF1, USF2 and HL were measured in HepG2 cells cultured in normal-or high-glucose medium (4.5 and 22.5 mmol/l, respectively) and in livers of streptozotocin-treated rats.Results Nuclear extracts of cells cultured in high glucose contained 2.5±0.5-fold more USF1 and 1.4±0.2-fold more USF2 protein than cells cultured in normal glucose (mean± SD, n=3). This coincided with higher DNA binding of nuclear proteins to the USF consensus DNA binding site. Secretion of HL (2.9±0.5-fold), abundance of HL mRNA (1.5±0.2-fold) and HL (-685/+13) promoter activity (1.8± 0.3-fold) increased in parallel. In chromatin immunoprecipitation assays, the proximal HL promoter region was immunoprecipitated with anti-USF1 and anti-USF2 antibodies. Co-transfection with USF1 or USF2 cDNA stimulated HL promoter activity 6-to 16-fold. USF and glucose responsiveness were significantly reduced by removal of the −310E-box from the HL promoter. Silencing of the USF1 gene by RNA interference reduced glucose responsiveness of the HL (−685/+13) promoter region by 50%. The hyperglycaemia in streptozotocin-treated rats was associated with similar increases in USF abundance in rat liver nuclei, but not with increased binding of USF to the rat Hl promoter region. Conclusions/interpretation Glucose increases HL expression in HepG2 cells via elevation of USF1 and USF2. This mechanism may contribute to the development of the dyslipidaemia that is typical of type 2 diabetes.

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Anti-inflammatory effects of atorvastatin improve left ventricular function in experimental diabetic cardiomyopathy

Cited by 118 publications

References 43 publications

Vascular-Protective Effects of High-Density Lipoprotein Include the Downregulation of the Angiotensin II Type 1 Receptor

Vascular-Protective Effects of High-Density Lipoprotein Include the Downregulation of the Angiotensin II Type 1 Receptor

Therapeutic Potential of HDL in Cardioprotection and Tissue Repair

Glucose increases hepatic lipase expression in HepG2 liver cells through upregulation of upstream stimulatory factors 1 and 2

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