Statins Modulate Heat Shock Protein Expression and Enhance Retinal Ganglion Cell Survival after Transient Retinal Ischemia/Reperfusion In Vivo

Schmeer, Christian; Gámez, Adriana D.; Tausch, Svetlana; Witte, Otto W.; Isenmann, Stefan

doi:10.1167/iovs.07-1597

Cited by 39 publications

(26 citation statements)

References 43 publications

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“…HSP-27 is a small HSP regulated by cellular stress. For example, in rat retinal ischaemia models, HSP-27 is upregulated and the protection of retina from ischaemia-reperfusion stress is accompanied by a reduction in HSP-27 [43]. In our experiments, we found HSP-27 colocalised with GFAP in the inner retina up to the inner nuclear layer, suggesting that astrocytes and Müller cells produced HSP-27 upon stress.…”

Section: Discussionsupporting

confidence: 55%

Low-dose erythropoietin inhibits oxidative stress and early vascular changes in the experimental diabetic retina

et al. 2010

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Aims/hypothesis Diabetic retinopathy is the result of increased oxidative and nitrosative stress induced by chronic hyperglycaemia, and affects the vasculature and the neuroglia. Erythropoietin is a neuroprotective and an endothelial survival factor. We assessed the effect of suberythropoietic epoetin delta doses on variables of oxidative stress in target tissues of diabetic complications and on pericyte loss in the diabetic retina. Methods We administered epoetin delta to streptozotocininduced diabetic Wistar rats at doses of 384 IU/kg body weight once weekly or 128 IU/kg body weight three times a week. The treatment lasted for 3 months. Oxidative stress and formation of AGEs were assessed by immunoblotting, expression of Ang-2 (also known as Angpt2) by RT-PCR, activation of protein kinase B (AKT) and heat shock protein (HSP)-27 levels by immunofluorescence, and incipient retinal vascular changes by quantitative morphometry of retinal digest preparations. Results Diabetes increased variables of oxidative stress and nitrosative stress (N ε -carboxymethyl-lysine, nitrotyrosine and methylglyoxal-type AGEs) in retina, kidney and heart of diabetic rats. Epoetin delta reduced oxidative and nitrosative stress in all tissues, and AGEs in the retina. It also reduced increased retinal Ang-2 expression and pericyte loss, and ameliorated p-AKT and HSP-27 levels. Conclusions/interpretation Epoetin delta has antioxidative properties in organs affected by diabetes and may prevent incipient microvascular damage in the diabetic retina.

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Section: Discussionsupporting

confidence: 55%

Low-dose erythropoietin inhibits oxidative stress and early vascular changes in the experimental diabetic retina

et al. 2010

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“…It has been shown that statins (HMG-CoA reductase inhibitors) may increase the levels of HSP27 in neural tissue [24] and that HSP27 is affected by pathways related to the RAS [25]. In our study the patients with type 2 diabetes had a greater proportion of individuals on statin and RAS inhibitor therapy compared with controls.…”

Section: Hsp27 and Medicationmentioning

confidence: 51%

Heat shock protein 27 is associated with better nerve function and fewer signs of neuropathy

et al. 2011

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Aims/hypothesis High levels of serum heat shock protein 27 (sHSP27) have been associated with distal symmetric polyneuropathy in patients with type 1 diabetes. Our objective was to investigate the association between sHSP27, neuropathic signs and nerve function in individuals with normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and type 2 diabetes. Methods Participants were recruited consecutively from the population-based Västerbotten Intervention Program (NGT, n=39, IGT, n=29, and type 2 diabetes, n=51) and were matched for age and sex. sHSP27 levels were measured and nerve conduction studies were performed (peroneal and sural nerves). z Scores for each nerve conduction measure were calculated and compiled into a composite z score for the leg. Neuropathy disability score (NDS) was used to assess neuropathic signs. Results Patients with diabetes had significantly lower sHSP27 levels (geometric mean sHSP27 206 pg/ml, 95% CI 142, 299) than those with IGT (geometric mean sHSP27 455 pg/ml, 95% CI 319, 650, p<0.05) and controls (geometric mean sHSP27 361 pg/ml, 95% CI 282, 461, p<0.05). Participants with few signs of neuropathy (first tertile, NDS ≤2) had significantly higher sHSP27 levels (geometric mean sHSP27 401 pg/ml, 95% CI 310, 520) than participants with many signs (third tertile, NDS ≥7) (geometric mean sHSP27 192 pg/ml, 95% CI 128, 288, p=0.007). The highest sHSP27 tertile was associated with better nerve function, adjusted for age, sex, statin medication and HbA 1c (OR 2.51, 95% CI 1.25, 5.05, p<0.05). Conclusions/interpretation High sHSP27 levels were associated with better nerve function and fewer neuropathic signs in NGT, IGT and type 2 diabetes.

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“…An effect of statin on HSPs expression has been previously observed in other tissues, such as human placental cells line [57] and rat retina during ischemia [58]. Together with the decrease of muscle plasmalogens, a sub-class of ether phospholipids involved in protection against oxidative damage [39], these effects suggest an accentuated sensitivity of statin-treated muscles to oxidative stress.…”

Section: Detoxification Systemsmentioning

confidence: 76%

Statin or fibrate chronic treatment modifies the proteomic profile of rat skeletal muscle

Camerino

Pellegrino

Brocca

et al. 2011

Biochemical Pharmacology

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Statins and fibrates can cause myopathy. To further understand the causes of the damage we performed a proteome analysis in fast-twitch skeletal muscle of rats chronically treated with different hypolipidemic drugs. The proteomic maps were obtained from extensor digitorum longus (EDL) muscles of rats treated for 2-months with 10mg/kg atorvastatin, 20mg/kg fluvastatin, 60mg/kg fenofibrate and control rats. The proteins differentially expressed were identified by mass spectrometry and further analysed by immunoblot analysis. We found a significant modification in 40 out of 417 total spots analysed in atorvastatin treated rats, 15 out of 436 total spots in fluvastatin treated rats and 21 out of 439 total spots in fenofibrate treated rats in comparison to controls. All treatments induced a general tendency to a down-regulation of protein expression; in particular, atorvastatin affected the protein pattern more extensively with respect to the other treatments.Energy production systems, both oxidative and glycolytic enzymes and creatine kinase, were downregulated following atorvastatin administration, whereas fenofibrate determined mostly alterations in glycolytic enzymes and creatine kinase, oxidative enzymes being relatively spared. Additionally, all treatments resulted in some modifications of proteins involved in cellular defenses against oxidative stress, such as heat shock proteins, and of myofibrillar proteins. These results were confirmed by immunoblot analysis. In conclusions, the proteomic analysis showed that either statin or fibrate administration can modify the expression of proteins essential for skeletal muscle function suggesting potential mechanisms for statin myopathy.

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Statins Modulate Heat Shock Protein Expression and Enhance Retinal Ganglion Cell Survival after Transient Retinal Ischemia/Reperfusion In Vivo

Cited by 39 publications

References 43 publications

Low-dose erythropoietin inhibits oxidative stress and early vascular changes in the experimental diabetic retina

Low-dose erythropoietin inhibits oxidative stress and early vascular changes in the experimental diabetic retina

Heat shock protein 27 is associated with better nerve function and fewer signs of neuropathy

Statin or fibrate chronic treatment modifies the proteomic profile of rat skeletal muscle

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