Cardiac Fibroblast p38 MAPK: A Critical Regulator of Myocardial Remodeling.

The cardiac fibroblast is a remarkably versatile cell type that coordinates inflammatory, fibrotic and hypertrophic responses in the heart through a complex array of intracellular and intercellular signaling mechanisms. One important signaling node that has been identified involves p38 MAPK; a family of kinases activated in response to stress and inflammatory stimuli that modulates multiple aspects of cardiac fibroblast function, including inflammatory responses, myofibroblast differentiation, extracellular matrix turnover and the paracrine induction of cardiomyocyte hypertrophy. This review explores the emerging importance of the p38 MAPK pathway in cardiac fibroblasts, describes the molecular mechanisms by which it regulates the expression of key genes, and highlights its potential as a therapeutic target for reducing adverse myocardial remodeling

Channelling the Force to Reprogram the Matrix: Mechanosensitive Ion Channels in Cardiac Fibroblasts

Cardiac fibroblasts (CF) play a pivotal role in preserving myocardial function and integrity of the heart tissue after injury, but also contribute to future susceptibility to heart failure. CF sense changes to the cardiac environment through chemical and mechanical cues that trigger changes in cellular function. In recent years, mechanosensitive ion channels have been implicated as key modulators of a range of CF functions that are important to fibrotic cardiac remodelling, including cell proliferation, myofibroblast differentiation, extracellular matrix turnover and paracrine signalling. To date, seven mechanosensitive ion channels are known to be functional in CF: the cation non-selective channels TRPC6, TRPM7, TRPV1, TRPV4 and Piezo1, and the potassium-selective channels TREK-1 and KATP. This review will outline current knowledge of these mechanosensitive ion channels in CF, discuss evidence of the mechanosensitivity of each channel, and detail the role that each channel plays in cardiac remodelling. By better understanding the role of mechanosensitive ion channels in CF, it is hoped that therapies may be developed for reducing pathological cardiac remodelling

Trust, confidence, and equity affect the legitimacy of natural resource governance

ArticleSocial-ecological systems are often highly complex, making effective governance a considerable challenge. In large, heterogeneous systems, hierarchical institutional regimes may be efficient, but effective management outcomes are dependent on stakeholder support. This support is shaped by perceptions of legitimacy, which risks being undermined where resource users are not engaged in decision-making. Although legitimacy is demonstrably critical for effective governance, less is known about the factors contributing to stakeholders’ perceptions of legitimacy or how these perceptions are socially differentiated. We quantitatively assessed stakeholder perceptions of legitimacy (indicated by support for rules) and their contributory factors among 307 commercial fishers and tourism operators in Australia’s Great Barrier Reef Marine Park. Legitimacy was most strongly associated with trust in information from governing bodies, followed by confidence in institutional performance and the equity of management outcomes. Legitimacy differed both within and among resource user groups, which emphasizes the heterogeneous nature of commonly defined stakeholder groups. Overall, tourism operators perceived higher legitimacy than did commercial fishers, which was associated with higher trust in information from management agencies. For fishers, higher levels of trust were associated with: (1) engagement in fisheries that had high subsector cohesion and positive previous experiences of interactions with governing bodies; (2) location in areas with greater proximity to sources of knowledge, resources, and decision-making; and (3) engagement in a Reef Guardian program. These findings highlight the necessity of strategies and processes to build trust among all user groups in large social-ecological systems such as the Great Barrier Reef Marine Park. Furthermore, the social differentiation of perceptions that were observed within user groups underscores the importance of targeted strategies to engage groups that may not be heard through traditional governance channels.The Social and Ecological Long Term Monitoring Program (SELTMP) for the Great Barrier Reef Marine Park was established in 2011 with funding provided by the Australian Government under the National Environment Research Program (NERP). We thank the SELTMP team for their support and collaboration. We also sincerely thank the commercial fishers and tourism operators that were part of this research and the interviewers that were involved. The arguments presented here are the sole responsibility of the authors. This paper was developed in a workshop funded by the Julius Career Award, the Commonwealth Scientific and Industrial Research Organisation (CSIRO), and the Environment and Sustainability theme of the University of Exeter’s Humanities and Social Science Strategy. The authors acknowledge additional support from the University of Exeter’s Outward Mobility Fund (R. T.), the Australian Research Council (T. M., A. A., B. J. B.), CSIRO (J. A.), and AusAID (A. A.)

Cardiac fibroblast-specific p38α MAP kinase promotes cardiac hypertrophy via a putative paracrine interleukin-6 signaling mechanism

Recent studies suggest that cardiac fibroblast-specific p38α MAPK contributes to the development of cardiac hypertrophy, but the underlying mechanism is unknown. Our study used a novel fibroblast-specific, tamoxifen-inducible p38α knockout (KO) mouse line to characterize the role of fibroblast p38α in modulating cardiac hypertrophy, and we elucidated the mechanism. Myocardial injury was induced in tamoxifen-treated Cre-positive p38α KO mice or control littermates via chronic infusion of the β-adrenergic receptor agonist isoproterenol. Cardiac function was assessed by pressure-volume conductance catheter analysis and was evaluated for cardiac hypertrophy at tissue, cellular, and molecular levels. Isoproterenol infusion in control mice promoted overt cardiac hypertrophy and dysfunction (reduced ejection fraction, increased end systolic volume, increased cardiac weight index, increased cardiomyocyte area, increased fibrosis, and up-regulation of myocyte fetal genes and hypertrophy-associated microRNAs). Fibroblast-specific p38α KO mice exhibited marked protection against myocardial injury, with isoproterenol-induced alterations in cardiac function, histology, and molecular markers all being attenuated. In vitro mechanistic studies determined that cardiac fibroblasts responded to damaged myocardium by secreting several paracrine factors known to induce cardiomyocyte hypertrophy, including IL-6, whose secretion was dependent upon p38α activity. In conclusion, cardiac fibroblast p38α contributes to cardiomyocyte hypertrophy and cardiac dysfunction, potentially via a mechanism involving paracrine fibroblast-to-myocyte IL-6 signaling.-Bageghni, S. A., Hemmings, K. E., Zava, N., Denton, C. P., Porter, K. E., Ainscough, J. F. X., Drinkhill, M. J., Turner, N. A. Cardiac fibroblast-specific p38α MAP kinase promotes cardiac hypertrophy via a putative paracrine interleukin-6 signaling mechanism

Role of the geosphere in deep nuclear waste disposal – An England and Wales perspective

To dispose permanently of its higher activity nuclear waste England and Wales have chosen deep geological disposal as the most appropriate solution currently available. The purpose of this paper is to describe the main geological features, events and processes relevant to England and Wales that will need to be considered to demonstrate that a site is suitable for a geological disposal facility (GDF). England and Wales are in the early stages of a GDF siting process in which areas of interest are being evaluated using mainly existing data from surface mapping and hydrocarbon exploration and production. Sites are evaluated consistently under six overarching headings, three of which are impacted by their geological setting – safety, engineering feasibility and value for money. “Suitable” geology is that which is safe during the operational and long-term post-closure period, which could have a GDF and its accessways constructed within it, and which delivers value for money. A GDF needs to fulfil dual safety functions wherever it is located: long-term containment of radionuclides, and isolation of the waste from human actions and from natural processes such as glaciations and earthquakes. The role of the geosphere in delivering these safety functions is to provide a low-flux groundwater environment with geochemical conditions that minimise degradation of the engineered components of the GDF, to promote retention of mobilised radionuclides, and to protect the waste from the impacts of humans and natural processes. The containment function of a GDF is provided by a combination of rock and engineering generally referred to as the multibarrier system. It comprises the engineered barriers – solid wasteforms, canisters, buffers, backfill materials, plugs and seals – that work together with the rock to ensure long-term containment. The GDF Programme in England and Wales seeks to identify suitable geological environments for which bespoke engineered barriers can be tailored to optimize the performance of the multibarrier system. The post-closure period over which independent regulators will require a safety case to demonstrate the long-term containment and isolation capabilities of a GDF is up to 1 million years. The long timescales make post-closure safety assessments a unique feature of deep geological disposal programmes. A comprehensive site characterization programme will use information mostly from seismic surveying and deep investigation boreholes to establish adequate rock availability (host rock depth, thickness, areal extent and compartmentalisation), suitable properties and behaviour of the deep geological environment, and the constructability and operability of a potential GDF site including its surface to subsurface access ways. Nuclear Waste Services, the organisation tasked with developing a GDF in England and Wales, is currently engaged with four Community Partnerships through a volunteer siting process: three in west Cumbria, and one on the English east coast in Theddlethorpe, Lincolnshire. In all of these areas Mesozoic claystones have been provisionally identified as potentially suitable GDF host rocks and are being investigated further, with a dedicated 3D seismic survey acquired off the coast of Cumbria in 2022. The main conclusion to be drawn from this paper is that a GDF could be sited in a large number of geological settings in England and Wales, and that the success of the current siting process will largely depend on engaging effectively with willing communities and building enduring relationships with them

Aberrant phenotype in human endothelial cells of diabetic origin: Implications for saphenous vein graft failure?

Type 2 diabetes (T2DM) confers increased risk of endothelial dysfunction, coronary heart disease, and vulnerability to vein graft failure after bypass grafting, despite glycaemic control. This study explored the concept that endothelial cells (EC) cultured from T2DM and nondiabetic (ND) patients are phenotypically and functionally distinct. Cultured human saphenous vein-(SV-) EC were compared between T2DM and ND patients in parallel. Proliferation, migration, and in vitro angiogenesis assays were performed; western blotting was used to quantify phosphorylation of Akt, ERK, and eNOS. The ability of diabetic stimuli (hyperglycaemia, TNF-α, and palmitate) to modulate angiogenic potential of ND-EC was also explored. T2DM-EC displayed reduced migration (30%) and angiogenesis (40%) compared with ND-EC and a modest, nonsignificant trend to reduced proliferation. Significant inhibition of Akt and eNOS, but not ERK phosphorylation, was observed in T2DM cells. Hyperglycaemia did not modify ND-EC function, but TNF-α and palmitate significantly reduced angiogenic capacity (by 27% and 43%, resp.), effects mimicked by Akt inhibition. Aberrancies of EC function may help to explain the increased risk of SV graft failure in T2DM patients. This study highlights the importance of other potentially contributing factors in addition to hyperglycaemia that may inflict injury and long-term dysfunction to the homeostatic capacity of the endothelium

Tenascin C upregulates interleukin-6 expression in human cardiac myofibroblasts via toll-like receptor 4.

AIM: To investigate the effect of Tenascin C (TNC) on the expression of pro-inflammatory cytokines and matrix metalloproteinases in human cardiac myofibroblasts (CMF). METHODS: CMF were isolated and cultured from patients undergoing coronary artery bypass grafting. Cultured cells were treated with either TNC (0.1 μmol/L, 24 h) or a recombinant protein corresponding to different domains of the TNC protein; fibrinogen-like globe (FBG) and fibronectin type III-like repeats (TNIII 5-7) (both 1 μmol/L, 24 h). The expression of the pro-inflammatory cytokines; interleukin (IL)-6, IL-1β, TNFα and the matrix metalloproteinases; MMPs (MMP1, 2, 3, 9, 10, MT1-MMP) was assessed using real time RT-PCR and western blot analysis. RESULTS: TNC increased both IL-6 and MMP3 (P < 0.01) mRNA levels in cultured human CMF but had no significant effect on the other markers studied. The increase in IL-6 mRNA expression was mirrored by an increase in protein secretion as assessed by enzyme-linked immunosorbant assay (P < 0.01). Treating CMF with the recombinant protein FBG increased IL-6 mRNA and protein (P < 0.01) whereas the recombinant protein TNIII 5-7 had no effect. Neither FBG nor TNIII 5-7 had any significant effect on MMP3 expression. The expression of toll-like receptor 4 (TLR4) in human CMF was confirmed by real time RT-PCR, western blot and immunohistochemistry. Pre-incubation of cells with TLR4 neutralising antisera attenuated the effect of both TNC and FBG on IL-6 mRNA and protein expression. CONCLUSION: TNC up-regulates IL-6 expression in human CMF, an effect mediated through the FBG domain of TNC and via the TLR4 receptor

Cellular mechanisms by which proinsulin C-peptide prevents insulin-induced neointima formation in human saphenous vein

AIMS/HYPOTHESIS: Endothelial cells (ECs) and smooth muscle cells (SMCs) play key roles in the development of intimal hyperplasia in saphenous vein (SV) bypass grafts. In diabetic patients, insulin administration controls hyperglycaemia but cardiovascular complications remain. Insulin is synthesised as a pro-peptide, from which C-peptide is cleaved and released into the circulation with insulin; exogenous insulin lacks C-peptide. Here we investigate modulation of human SV neointima formation and SV-EC and SV-SMC function by insulin and C-peptide. METHODS: Effects of insulin and C-peptide on neointima formation (organ cultures), EC and SMC proliferation (cell counting), EC migration (scratch wound), SMC migration (Boyden chamber) and signalling (immunoblotting) were examined. A real-time RT-PCR array identified insulin-responsive genes, and results were confirmed by real-time RT-PCR. Targeted gene silencing (siRNA) was used to assess functional relevance. RESULTS: Insulin (100 nmol/l) augmented SV neointimal thickening (70% increase, 14 days), SMC proliferation (55% increase, 7 days) and migration (150% increase, 6 h); effects were abrogated by 10 nmol/l C-peptide. C-peptide did not affect insulin-induced Akt or extracellular signal-regulated kinase signalling (15 min), but array data and gene silencing implicated sterol regulatory element binding transcription factor 1 (SREBF1). Insulin (1-100 nmol/l) did not modify EC proliferation or migration, whereas 10 nmol/l C-peptide stimulated EC proliferation by 40% (5 days). CONCLUSIONS/INTERPRETATION: Our data support a causative role for insulin in human SV neointima formation with a novel counter-regulatory effect of proinsulin C-peptide. Thus, C-peptide can limit the detrimental effects of insulin on SMC function. Co-supplementing insulin therapy with C-peptide could improve therapy in insulin-treated patients