ORCID Profile
0000-0003-1465-7372
Current Organisation
National Institutes of Health
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Publisher: Wiley
Date: 13-06-2023
Abstract: The increasing incidence of cardiovascular disease (CVD) has led to a significant ongoing need to address this surgically through coronary artery bypass grafting (CABG) and percutaneous coronary interventions (PCI). From this, there continues to be a substantial burden of mortality and morbidity due to complications arising from endothelial damage, resulting in restenosis. Whilst mast cells (MC) have been shown to have a causative role in atherosclerosis and other vascular diseases, including restenosis due to vein engraftment here, we demonstrate their rapid response to arterial wire injury, recapitulating the endothelial damage seen in PCI procedures. Using wild‐type mice, we demonstrate accumulation of MC in the femoral artery post‐acute wire injury, with rapid activation and degranulation, resulting in neointimal hyperplasia, which was not observed in MC‐deficient Kit W‐sh/W‐sh mice. Furthermore, neutrophils, macrophages, and T cells were abundant in the wild‐type mice area of injury but reduced in the Kit W‐sh/W‐sh mice. Following bone‐marrow‐derived MC (BMMC) transplantation into Kit W‐sh/W‐sh mice, not only was the neointimal hyperplasia induced, but the neutrophil, macrophage, and T‐cell populations were also present in these transplanted mice. To demonstrate the utility of MC as a target for therapy, we administered the MC stabilizing drug, disodium cromoglycate (DSCG) immediately following arterial injury and were able to show a reduction in neointimal hyperplasia in wild‐type mice. These studies suggest a critical role for MC in inducing the conditions and coordinating the detrimental inflammatory response seen post‐endothelial injury in arteries undergoing revascularization procedures, and by targeting the rapid MC degranulation immediately post‐surgery with DSCG, this restenosis may become a preventable clinical complication.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-03-2023
DOI: 10.1161/CIRCRESAHA.121.320541
Abstract: Mutations in BMPR2 (bone morphogenetic protein receptor 2) are associated with familial and sporadic pulmonary arterial hypertension (PAH). The functional and molecular link between loss of BMPR2 in pulmonary artery smooth muscle cells (PASMC) and PAH pathogenesis warrants further investigation, as most investigations focus on BMPR2 in pulmonary artery endothelial cells. Our goal was to determine whether and how decreased BMPR2 is related to the abnormal phenotype of PASMC in PAH. SMC-specific Bmpr2 −/− mice ( BKO SMC ) were created and compared to controls in room air, after 3 weeks of hypoxia as a second hit, and following 4 weeks of normoxic recovery. Echocardiography, right ventricular systolic pressure, and right ventricular hypertrophy were assessed as indices of pulmonary hypertension. Proliferation, contractility, gene and protein expression of PASMC from BKO SMC mice, human PASMC with BMPR2 reduced by small interference RNA, and PASMC from PAH patients with a BMPR2 mutation were compared to controls, to investigate the phenotype and underlying mechanism. BKO SMC mice showed reduced hypoxia-induced vasoconstriction and persistent pulmonary hypertension following recovery from hypoxia, associated with sustained muscularization of distal pulmonary arteries. PASMC from mutant compared to control mice displayed reduced contractility at baseline and in response to angiotensin II, increased proliferation and apoptosis resistance. Human PASMC with reduced BMPR2 by small interference RNA, and PASMC from PAH patients with a BMPR2 mutation showed a similar phenotype related to upregulation of pERK1/2 (phosphorylated extracellular signal related kinase 1/2)-pP38-pSMAD2/3 mediating elevation in ARRB2 (β-arrestin2), pAKT (phosphorylated protein kinase B) inactivation of GSK3-beta, CTNNB1 (β-catenin) nuclear translocation and reduction in RHOA (Ras homolog family member A) and RAC1 (Ras-related C3 botulinum toxin substrate 1). Decreasing ARRB2 in PASMC with reduced BMPR2 restored normal signaling, reversed impaired contractility and attenuated heightened proliferation and in mice with inducible loss of BMPR2 in SMC, decreasing ARRB2 prevented persistent pulmonary hypertension. Agents that neutralize the elevated ARRB2 resulting from loss of BMPR2 in PASMC could prevent or reverse the aberrant hypocontractile and hyperproliferative phenotype of these cells in PAH.
Publisher: Wiley
Date: 26-01-2016
DOI: 10.1111/RESP.12729
Abstract: Pulmonary arterial hypertension (PAH) continues to be a fatal disease and is associated with downregulation of bone morphogenetic protein receptor type-2 (BMPR2). Our approach is to upregulate BMPR2 in the pulmonary vasculature allowing us to examine the changes in endothelial cell signalling and better understand what pathways are altered when disease is attenuated using this treatment approach. We used gene delivery of BMPR2 to human pulmonary endothelial cells to investigate downstream signalling, then assessed the impact of this approach on downstream signalling in vivo in rats with PAH using the monocrotaline (MCT) model. Gene delivery of BMPR2 leads to an increase in BMPR2 protein expression, and this is associated with increased Smad1/5/8 and reduced Smad2/3 signalling. Additionally, we have found that BMPR2 modulation has effects on non-Smad signalling with increases found in phosphoinositide-3 kinase (PI3K) and a decrease in phosphorylated-p38-mitogen activated protein kinase (p38-MAPK) in vivo. These findings are associated with amelioration of PAH (reduced right ventricular, mean pulmonary artery pressures and Fulton Index). These results indicate that the therapeutic effect of BMPR2 gene delivery on PAH is associated with a switch between TGF-β-Smad2/3 signalling to BMPR2-Smad1/5/8 signalling. This supports the further development of this treatment approach.
Publisher: Wiley
Date: 21-12-2016
DOI: 10.1111/RESP.12712
Abstract: Idiopathic, familial and secondary pulmonary arterial hypertension (PAH) are associated with reduced bone morphogenetic protein receptor type 2 (BMPR2) expression, and in some contexts, TGF-β upregulation. Our aims were to assess BMPR2 gene therapy in a PAH mouse model and to assess the impact on TGF-β signalling. Using a targeted in vivo gene delivery approach, we assessed the impact of BMPR2 gene delivery in a transgenic mouse model in which PAH was first induced by doxycycline driven expression of a dominant negative BMPR2 mutant (R899X). We also assessed the impact of BMPR2 gene delivery on TGF-β-induced changes in cell signalling in human pulmonary vascular endothelial and smooth muscle cells. In the mouse model, changes in TGF-β levels were not detected, but BMPR2 gene delivery reversed the increase in right ventricle systolic pressure (RVSP) and Fulton Index (FI), associated with a trend to increased pulmonary endothelial nitric oxide synthase (eNOS) gene expression. In vitro, BMPR2 gene transfer reduced TGF-β effects on Smad2, Smad1/5/8 and Erk1/2 phosphorylation in human pulmonary arterial smooth muscle cells (HPASMC). BMPR2 was also found to upregulate nitric oxide (NO) production in lung derived human microvascular endothelial cells (HMVEC-L). This study provides further evidence that BMPR2 modulation may have therapeutic potential. See Editorial, page 406.
Publisher: Springer Science and Business Media LLC
Date: 17-03-2023
DOI: 10.1038/S41467-023-36941-Y
Abstract: Neutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases pathomechanisms that regulate extravasation of damaging immune cells into surrounding tissues are poorly understood. Here we identified three unrelated boys with perinatal-onset of neutrophilic cutaneous small vessel vasculitis and systemic inflammation. Two patients developed liver fibrosis in their first year of life. Next-generation sequencing identified two de novo truncating variants in the Src-family tyrosine kinase, LYN , p.Y508*, p.Q507* and a de novo missense variant, p.Y508F, that result in constitutive activation of Lyn kinase. Functional studies revealed increased expression of ICAM-1 on induced patient-derived endothelial cells (iECs) and of β2-integrins on patient neutrophils that increase neutrophil adhesion and vascular transendothelial migration (TEM). Treatment with TNF inhibition improved systemic inflammation and liver fibrosis resolved on treatment with the Src kinase inhibitor dasatinib. Our findings reveal a critical role for Lyn kinase in modulating inflammatory signals, regulating microvascular permeability and neutrophil recruitment, and in promoting hepatic fibrosis.
Location: United States of America
Location: Australia
No related grants have been discovered for Rebecca Harper.