Lentiviral gene transfer to reduce atherosclerosis progression by long-term CC-chemokine inhibition

Bursill, Christina A.; McNeill, Eileen; Wang, L; Hibbitt, Olivia; Wade‐Martins, Richard; Paterson, David J.; Greaves, David R.; Channon, Keith M.

doi:10.1038/gt.2008.141

Cited by 31 publications

(35 citation statements)

References 34 publications

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“…Similarly, non-diabetic mice were assigned to one of three groups (n08 per group) and were injected with PBS (C), LV-scr (C+LV-scr) or LV-shTctp1 (C+LV-shTctp1). The animals were given the selected treatment on days 0 and 7 via hydrodynamic tail vein injection as described previously [17]. Briefly, mice were maintained under isoflurane anaesthesia and given injections into the tail vein within 10 s of 1 ml of PBS alone or PBS containing 4 × 10 8 TU of lentivirus.…”

Section: Methodsmentioning

confidence: 99%

Translationally controlled tumour protein is associated with podocyte hypertrophy in a mouse model of type 1 diabetes

Kim

Nam

et al. 2012

Diabetologia

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Aims/hypothesis Translationally controlled tumour protein (TCTP) is thought to be involved in cell growth by regulating mTOR complex 1 (mTORC1) signalling. As diabetes characteristically induces podocyte hypertrophy and mTORC1 has been implicated in this process, TCTP may have a role in the pathogenesis of diabetes-induced podocyte hypertrophy. Methods We investigated the effects and molecular mechanisms of TCTP in diabetic mice and in high glucose-stimulated cultured podocytes. To characterise the role of TCTP, we conducted lentivirus-mediated gene silencing of TCTP both in vivo and in vitro. Results Glomerular production of TCTP was significantly higher in streptozotocin induced-diabetic DBA/2J mice than in control animals. Double-immunofluorescence staining for TCTP and synaptopodin revealed that podocyte was the principal cell responsible for this increase. TCTP knockdown attenuated the activation of mTORC1 downstream effectors and the overproduction of cyclin-dependent kinase inhibitors (CKIs) in diabetic glomeruli, along with a reduction in proteinuria and a decrease in the sizes of podocytes as well as glomeruli. In addition, knockdown of TCTP in db/db mice prevented the development of diabetic nephropathy, as indicated by the amelioration of proteinuria, mesangial expansion, podocytopenia and glomerulosclerosis. In accordance with the in vivo data, TCTP inhibition abrogated high glucose-induced hypertrophy in cultured podocytes, which was accompanied by the downregulation of mTORC1 effectors and CKIs. Conclusions/interpretation These findings suggest that TCTP might play an important role in the process of podocyte hypertrophy under diabetic conditions via the regulation of mTORC1 activity and the induction of cell-cycle arrest.

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Section: Methodsmentioning

confidence: 99%

Translationally controlled tumour protein is associated with podocyte hypertrophy in a mouse model of type 1 diabetes

Kim

Nam

et al. 2012

Diabetologia

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“…Blocking monoclonal antibodies (mAbs) tested in animal models of atherogenesis include a reagent that blocks murine chemokines CCL2 and MCP-5 (Lutgens et al, 2005). Broad spectrum CC chemokine blockade in Apoe 2/2 mice has been tested using in vivo delivery of a viral CC chemokine binding protein derived from poxvirus (known as 35K or vCCI) (Bursill et al, 2004;Bursill et al, 2009).…”

Section: Luchtefeld Et Al 2010mentioning

confidence: 99%

CC Chemokine Receptors and Chronic Inflammation—Therapeutic Opportunities and Pharmacological Challenges

2013

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“…Vaccinia viruses encodes a 35 kDa pan-CC chemokine-binding protein, vCCI (viral chemoline inhibitor)/35K, which binds many CC chemokines with high affinity making it a very efficient broad-spectrum inhibitor of CC chemokine activity. Expression of the 35K molecule in vivo using both short-term high-level adenoviral delivery or longterm lentiviral delivery causes a potent inhibition of atherogenesis [44,45]. Additionally, this molecule is effective in ameliorating vein-graft disease in a murine model [46].…”

Section: Chemokines and Atherosclerosismentioning

confidence: 99%

Inflammatory cell recruitment in cardiovascular disease: murine models and potential clinical applications

2010

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Atherosclerosis is the pathological process that underlies the development of cardiovascular disease, a leading cause of mortality. Atherosclerotic plaque formation is driven by the recruitment of inflammatory monocytes into the artery wall, their differentiation into macrophages and the subsequent transformation of macrophages into cholesterol-laden foam cells. Models of hypercholesterolaemia such as the ApoE (apolipoprotein E)-/- mouse and the application of transgenic technologies have allowed us to undertake a thorough dissection of the cellular and molecular biology of the atherosclerotic disease process. Murine models have emphasized the central role of inflammation in atherogenesis and have been instrumental in the identification of adhesion molecules that support monocyte recruitment, scavenger receptors that facilitate cholesterol uptake by macrophages and other macrophage activation receptors. The study of mice deficient in multiple members of the chemokine family, and their receptors, has shown that chemokines play a critical role in promoting atherosclerotic plaque formation. In the present review, we will discuss novel therapeutic avenues for the treatment of cardiovascular disease that derive directly from our current understanding of atherogenesis gained in experimental animal models.

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Lentiviral gene transfer to reduce atherosclerosis progression by long-term CC-chemokine inhibition

Cited by 31 publications

References 34 publications

Translationally controlled tumour protein is associated with podocyte hypertrophy in a mouse model of type 1 diabetes

Translationally controlled tumour protein is associated with podocyte hypertrophy in a mouse model of type 1 diabetes

CC Chemokine Receptors and Chronic Inflammation—Therapeutic Opportunities and Pharmacological Challenges

Inflammatory cell recruitment in cardiovascular disease: murine models and potential clinical applications

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