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Li Y.,Baker IDI Heart and Diabetes Institute | Li Y.,Center for Inflammatory Diseases | Kanellakis P.,Baker IDI Heart and Diabetes Institute | Hosseini H.,Baker IDI Heart and Diabetes Institute | And 11 more authors.
Cardiovascular Research | Year: 2016

Aims Atherosclerosis-related deaths from heart attacks and strokes remain leading causes of global mortality, despite the use of lipid-lowering statins. Thus, there is an urgent need to develop additional therapies. Methods and results Reports that NKT cells promote atherosclerosis and an NKT cell CD1d-dependent lipid antagonist (DPPE-PEG350, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N[methoxy(polyethyleneglycol)-350]) reduces allergen-induced inflammation led us to investigate its therapeutic potential in preventing the development and progression of experimental atherosclerosis. DPPE-PEG350 was administered to hyperlipidaemic ApoE-/- mice with/without established atherosclerosis. Atherosclerosis and immune cells were assessed in the aortic sinus lesions. Lesion expression of monocyte chemoattractant protein-1 (MCP-1) and vascular cell adhesion protein-1 (VCAM-1) responsible for inflammatory immune cell recruitment as well as mRNA expression of IFNγ and its plasma levels were investigated. Necrotic cores and lesion smooth muscle and collagen contents important in plaque stability were determined as were plasma lipid levels. DPPE-PEG350 reduced atherosclerosis development and delayed progression of established atherosclerosis without affecting plasma lipids. CD4 and CD8 T cells and B cells in atherosclerotic lesions were decreased in DPPE-PEG350-Treated mice. Lesion MCP-1 and VCAM-1 protein expression and necrotic core size were reduced without affecting lesion smooth muscle and collagen content. IFNγ and lymphocytes were unaffected by the treatment. Conclusion The attenuation of progression of established atherosclerosis together with reduced development of atherosclerosis in hyperlipidaemic mice by the NKT antagonist, without affecting NKT cell or other lymphocyte numbers, suggests that targeting lesion inflammation via CD1d-dependent activation of NKT cells using DPPE-PEG350 has a therapeutic potential in treating atherosclerosis. © 2015 Published on behalf of the European Society of Cardiology. All rights reserved The Author 2015.

Lim R.,MIMR PHI Institute of Medical ResearchVIC | Lim R.,Monash University | Muljadi R.,MIMR PHI Institute of Medical ResearchVIC | Koulaeva E.,Monash University | And 8 more authors.
Pediatric Research | Year: 2015

Background:Bronchopulmonary dysplasia (BPD) is one of the leading causes of morbidity and mortality in babies born prematurely, yet there is no curative treatment. In recent years, a number of inhibitors against TGFβ signaling have been tested for their potential to prevent neonatal injury associated with hyperoxia, which is a contributing factor of BPD. In this study, we assessed the contribution of activin A - a member of the TGFβ superfamily - to the development of hyperoxia-induced lung injury in neonatal mice.Methods:We placed newborn C57Bl6 mouse pups in continuous hyperoxia (85% O 2) to mimic many aspects of BPD including alveolar simplification and pulmonary inflammation. The pups were administered activin A receptor type IIB-Fc antagonist (ActRIIB-Fc) at 5 mg/kg or follistatin at 0.1 mg/kg on postnatal days 4, 7, 10, and 13.Results:Treatment with ActRIIB-Fc and follistatin protected against hyperoxia-induced growth retardation. ActRIIB-Fc also reduced pulmonary leukocyte infiltration, normalized tissue: airspace ratio and increased septal crest density. These findings were associated with reduced phosphorylation of Smad3 and decreased matrix metalloproteinase (MMP)-9 activity.Conclusion:This study suggests that activin A signaling may contribute to the pathology of bronchopulmonary dysplasia. Copyright © 2015 International Pediatric Research Foundation, Inc.

Lim R.,MIMR PHI Institute of Medical ResearchVIC | Lim R.,Monash University | Adhikari S.,MIMR PHI Institute of Medical ResearchVIC | Gurusinghe S.,MIMR PHI Institute of Medical ResearchVIC | And 10 more authors.
Placenta | Year: 2015

Introduction Pre-eclampsia remains a major cause of maternal and fetal morbidity and mortality. Despite intensive research over the last 50 years, significant therapeutic advances have yet to be realised. We recently reported on the role of activin A in the pathophysiology of pre-eclampsia, whereby a pre-eclampsia-like disease state was induced in pregnant mice through activin A infusion. Using the same animal model, the effects of inhibiting activin A signalling on this pre-eclampsia-like disease state have now been assessed with low molecular weight compounds structurally related to activin-receptor-like kinase (ALK) inhibitors. Methods 23 synthetic compounds were screened for ability to reduce activin A-induced free radical production in HUVECs. Further, following administration of activin A (50 μg) via a subcutaneous mini-osmotic pump from day 10 of pregnancy, the most active inhibitor, MKP-1-140A, (1 mg/kg) was also concomitantly administered via subcutaneous injections. Results Significant reductions in activin A-induced systolic blood pressure and urine albumin:creatinine ratio were observed with inhibitor-treated animals. However, these findings were accompanied by sustained elevation of liver enzymes and albumin extravasation in the brains of pregnant mice that received MKP-1-140A. Furthermore, inhibition of activin A signalling with MKP-1-140A failed to rescue fetal growth restriction, and treatment with MKP-1-140A alone resulted in craniofacial and karyotypic abnormalities. Discussion These data indicate that whilst inhibition of activin A signalling by the low molecular weight ALK kinase inhibitor, MKP-1-140A, reduced some of the physiological manifestations of pre-eclampsia, the potential for serious maternal and fetal side effects may preclude it from clinical applications. © 2015 Published by Elsevier Ltd. All rights reserved.

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