Donor Simvastatin Treatment Abolishes Rat Cardiac Allograft Ischemia/Reperfusion Injury and Chronic Rejection Through Microvascular Protection

Tuuminen, Raimo; Syrjälä, S.; Krebs, R.; Keränen, Mikko; Koli, Katri; Abo‐Ramadan, Usama; Neuvonen, Pertti J.; Tikkanen, Jussi; Nykänen, Antti; Lemström, Karl

doi:10.1161/circulationaha.110.005249

Cited by 67 publications

(57 citation statements)

References 48 publications

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“…[8][9][10] Furthermore, TGF-b mediates contraction of preretinal membranes. 11 TGF-b is induced in the vitreous in proliferative diabetic retinopathy and proliferative vitreoretinopathy.…”

Section: Introductionmentioning

confidence: 99%

High intravitreal TGF-β1 and MMP-9 levels in eyes with retinal vein occlusion

Tuuminen

Loukovaara

2014

Eye

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Purpose Vascular endothelial growth factor is a leading target to reduce macular oedema and improve visual acuity in patients with retinal vein occlusion (RVO), whereas the role of vascular destabilizing and fibroproliferative transforming growth factor (TGF)-b1 and matrix metalloproteinases (MMP)-2 and -9 in pathological manifestations of RVO is anticipated but less studied. Methods Undiluted vitreous samples were collected from three central RVO and one branch RVO eyes, all with neovascularization and fibrosis-related sight-threatening complications of RVO. Undiluted vitreous samples of 40 eyes operated due to nonischemic condition either macular hole or pucker were used as controls. Growth factor and protease concentrations were measured by ELISA and gelatin zymography. Results Vitreous concentrations of TGF-b1 (92.0 ± 17.4 pg/ml vs 18.3 ± 27.0 pg/ml, mean ± SD; P ¼ 0.002) and MMP-9 (847.9 ± 1196.4 AU/ml vs 87.7 ± 174.0 AU/ml; P ¼ 0.010) were higher in the eyes with ischemic RVO than in the controls. Conclusions High intravitreal levels of TGF-b1 and MMP-9 are found in RVO eyes having neovascular and fibrosis manifestation. Further studies are warranted to elucidate whether targeting TGF-b1 and MMP-9 could be beneficial in patients with ischemic RVO.

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“…[8][9][10] Furthermore, TGF-b mediates contraction of preretinal membranes. 11 TGF-b is induced in the vitreous in proliferative diabetic retinopathy and proliferative vitreoretinopathy.…”

Section: Introductionmentioning

confidence: 99%

High intravitreal TGF-β1 and MMP-9 levels in eyes with retinal vein occlusion

Tuuminen

Loukovaara

2014

Eye

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“…In chronic rejection transforming growth, factor-β1-induced microvascular endothelial-tomesenchymal transition and led to myocardial fibrosis. This effect was abolished by simvastatin treatment via inhibition of transforming growth factor-β1 [38].…”

Section: Mia-reperfusion Injury and Treatments With Antioxidantsmentioning

confidence: 97%

Role of Oxidative Stress in Cardiac Allograft Vasculopathy

Nair¹,

Góngora²,

Reynolds³

2013

OJOTS

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Cardiac Allograft Vasculopathy, an accelerated form of arterial occlusive disease, is the major cause of death in the long-term after heart transplantation. Multiple factors influence the initiation and progression of CAV. These include ischemia-reperfusion, dyslipidemia, insulin resistance, and hypertension due to the use of immunosuppressive agents, the direct effects of immunosuppressive agents on endothelial function, and viruses (CMV). Impaired endothelial function reflects abnormalities in the production or activity of several vasoactive substances. Disruption of the nitric oxide synthase (NOS) pathway leads to changes in vascular reactivity, structure, and interaction with circulating blood components. Since endothelium-derived nitric oxide (NO) suppresses vascular cell proliferation and vascular inflammation, a deficit in vascular NO facilitates development of CAV. The link between oxidative stress and CAV largely exists in the balance between free radical superoxide   2 O  generation and NO production. This review focuses on identifying the oxidative stress factors affecting CAV.

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“…We derived the simvastatin doses from dose-response studies performed by our colleagues in an experimental model of obliterative bronchiolitis and heart transplantation in the same rat strains as used here [14,15] . Simvastatin doses used in this study were 2 mg/kg/day for recipients and 5 mg/kg for donors.…”

Section: Experimental Designmentioning

confidence: 99%

Intensive Perioperative Simvastatin Treatment Protects from Chronic Kidney Allograft Injury

Palin

Savikko²,

Rintala³

et al. 2015

Am J Nephrol

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Background/Aims: Ischemia-reperfusion injury (IRI) and innate immune response augment adaptive immunity and may also trigger repair processes that lead to uncontrolled fibrosis and atherosclerosis as seen in chronic allograft injury. Simvastatin has been shown to protect from renal IRI in several experimental studies. The aim of this study was to examine the effect of donor simvastatin pretreatment and early initiation of recipient simvastatin treatment on chronic kidney allograft injury. Methods: A rat renal transplantation model was used. Simvastatin was administered perorally for donor (5 mg/kg) and/or for recipient (2 mg/kg) 2 hours before transplantation and/or as daily treatment starting on the first postoperative day (2 mg/kg/day). The study included 5 groups: (1) no simvastatin, (2) donor pretreatment, (3) daily recipient treatment, (4) donor pretreatment + daily recipient treatment and (5) donor pretreatment + recipient pretreatment + daily recipient treatment. The grafts were recovered at day 90 for histopathological and immunohistochemical analysis. Kidney function was followed weekly with serum creatinine, and 24-hour urine protein was measured 60 and 90 days after transplantation. Results: We found that donor and recipient simvastatin pretreatment combined with daily recipient treatment reduced graft inflammation and chronic allograft injury. Treatment using only statins started after transplantation reduced inflammation to some extent, but did not affect chronic kidney allograft injury. Pretreatment using only donor statins impaired graft function and increased proteinuria. Conclusion: Our data suggest that perioperative recipient statin treatment reduces inflammation and may protect the graft in the long term.

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Donor Simvastatin Treatment Abolishes Rat Cardiac Allograft Ischemia/Reperfusion Injury and Chronic Rejection Through Microvascular Protection

Cited by 67 publications

References 48 publications

High intravitreal TGF-β1 and MMP-9 levels in eyes with retinal vein occlusion

High intravitreal TGF-β1 and MMP-9 levels in eyes with retinal vein occlusion

Role of Oxidative Stress in Cardiac Allograft Vasculopathy

Intensive Perioperative Simvastatin Treatment Protects from Chronic Kidney Allograft Injury

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