Bcl-2 protein family: Implications in vascular apoptosis and atherosclerosis

Apoptosis has been recognized as a central component in the pathogenesis of atherosclerosis, in addition to the other human pathologies such as cancer and diabetes. The pathophysiology of atherosclerosis is complex, involving both apoptosis and proliferation at different phases of its progression. Oxidative modification of lipids and inflammation differentially regulate the apoptotic and proliferative responses of vascular cells during progression of the atherosclerotic lesion. Bcl-2 proteins act as the major regulators of extrinsic and intrinsic apoptosis signalling pathways and more recently it has become evident that they mediate the apoptotic response of vascular cells in response to oxidation and inflammation either in a provocative or an inhibitory mode of action. Here we address Bcl-2 proteins as major therapeutic targets for the treatment of atherosclerosis and underscore the need for the novel preventive and therapeutic interventions against atherosclerosis, which should be designed in the light of molecular mechanisms regulating apoptosis of vascular cells in atherosclerotic lesions

Experience of Health Leadership in Partnering With University-Based Researchers in Canada – A Call to “Re-imagine” Research

Background: Emerging evidence that meaningful relationships with knowledge users are a key predictor of research use has led to promotion of partnership approaches to health research. However, little is known about health system experiences of collaborations with university-based researchers, particularly with research partnerships in the area of health system design and health service organization. The purpose of the study was to explore the experience and perspectives of senior health managers in health service organizations, with health organization-university research partnerships. Methods: In-depth, semi-structured interviews (n = 25) were conducted with senior health personnel across Canada to explore their perspectives on health system research; experiences with health organization-university research partnerships; challenges to partnership research; and suggested actions for improving engagement with knowledge users and promoting research utilization. Participants, recruited from organizations with regional responsibilities, were responsible for system-wide planning and support functions. Results: Research is often experienced as unhelpful or irrelevant to decision-making by many within the system. Research, quality improvement (QI) and evaluation are often viewed as separate activities and coordinated by different responsibility areas. Perspectives of senior managers on barriers to partnership differed from those identified in the literature: organizational stress and restructuring, and limitations in readiness of researchers to work in the fast-paced healthcare environment, were identified as major barriers. Although the need for strong executive leadership was emphasized, “multi-system action” is needed for effective partnerships. Conclusion: Common approaches to research and knowledge translation are often not appropriate for addressing issues of health service design and health services organization. Nor is the research community providing expertise to many important activities that the healthcare system is taking to improve health services. A radical rethinking of how we prepare health service researchers; position research within the health system; and fund research activities and infrastructure is needed if the potential benefits of research are to be achieved. Lack of response to health system needs may contribute to research and ‘evidence-informed’ practice being further marginalized from healthcare operations. Interventions to address barriers must respond to the perspectives and experience of health leadership

Intracellular Function of Interleukin-1 Receptor Antagonist in Ischemic Cardiomyocytes

Background: Loss of cardiac myocytes due to apoptosis is a relevant feature of ischemic heart disease. It has been described in infarct and peri-infarct regions of the myocardium in coronary syndromes and in ischemia-linked heart remodeling. Previous studies have provided protection against ischemia-induced cardiomyocyte apoptosis by the anti-inflammatory cytokine interleukin-1 receptor-antagonist (IL-1Ra). Mitochondria triggering of caspases plays a central role in ischemia-induced apoptosis. We examined the production of IL-1Ra in the ischemic heart and, based on dual intra/extracellular function of some other interleukins, we hypothesized that IL-1Ra may also directly inhibit mitochondria-activated caspases and cardiomyocyte apoptosis. Methodology/Principal Findings: Synthesis of IL-1Ra was evidenced in the hearts explanted from patients with ischemic heart disease. In the mouse ischemic heart and in a mouse cardiomyocyte cell line exposed to long-lasting hypoxia, IL-1Ra bound and inhibited mitochondria-activated caspases, whereas inhibition of caspase activation was not observed in the heart of mice lacking IL-1Ra (Il-1ra−/−) or in siRNA to IL-1Ra-interfered cells. An impressive 6-fold increase of hypoxia-induced apoptosis was observed in cells lacking IL-1Ra. IL-1Ra down-regulated cells were not protected against caspase activation and apoptosis by knocking down of the IL-1 receptor, confirming the intracellular, receptor-independent, anti-apoptotic function of IL-1Ra. Notably, the inhibitory effect of IL-1Ra was not influenced by enduring ischemic conditions in which previously described physiologic inhibitors of apoptosis are neutralized. Conclusions/Significance: These observations point to intracellular IL-1Ra as a critical mechanism of the cell self-protection against ischemia-induced apoptosis and suggest that this cytokine plays an important role in the remodeling of heart by promoting survival of cardiomyocytes in the ischemic regions

An NF-κB and Slug Regulatory Loop Active in Early Vertebrate Mesoderm

BACKGROUND: In both Drosophila and the mouse, the zinc finger transcription factor Snail is required for mesoderm formation; its vertebrate paralog Slug (Snai2) appears to be required for neural crest formation in the chick and the clawed frog Xenopus laevis. Both Slug and Snail act to induce epithelial to mesenchymal transition (EMT) and to suppress apoptosis. METHODOLOGY & PRINCIPLE FINDINGS: Morpholino-based loss of function studies indicate that Slug is required for the normal expression of both mesodermal and neural crest markers in X. laevis. Both phenotypes are rescued by injection of RNA encoding the anti-apoptotic protein Bcl-xL; Bcl-xL's effects are dependent upon IκB kinase-mediated activation of the bipartite transcription factor NF-κB. NF-κB, in turn, directly up-regulates levels of Slug and Snail RNAs. Slug indirectly up-regulates levels of RNAs encoding the NF-κB subunit proteins RelA, Rel2, and Rel3, and directly down-regulates levels of the pro-apopotic Caspase-9 RNA. CONCLUSIONS/SIGNIFICANCE: These studies reveal a Slug/Snail–NF-κB regulatory circuit, analogous to that present in the early Drosophila embryo, active during mesodermal formation in Xenopus. This is a regulatory interaction of significance both in development and in the course of inflammatory and metastatic disease

Experience of Health Leadership in Partnering With University-Based Researchers in Canada – A Call to "Reimagine" Research

Background: Emerging evidence that meaningful relationships with knowledge users are a key predictor of research use has led to promotion of partnership approaches to health research. However, little is known about health system experiences of collaborations with university-based researchers, particularly with research partnerships in the area of health system design and health service organization. The purpose of the study was to explore the experience and perspectives of senior health managers in health service organizations, with health organization-university research partnerships. Methods: In-depth, semi-structured interviews (n = 25) were conducted with senior health personnel across Canada to explore their perspectives on health system research; experiences with health organization-university research partnerships; challenges to partnership research; and suggested actions for improving engagement with knowledge users and promoting research utilization. Participants, recruited from organizations with regional responsibilities, were responsible for system-wide planning and support functions. Results: Research is often experienced as unhelpful or irrelevant to decision-making by many within the system. Research, quality improvement (QI) and evaluation are often viewed as separate activities and coordinated by different responsibility areas. Perspectives of senior managers on barriers to partnership differed from those identified in the literature: organizational stress and restructuring, and limitations in readiness of researchers to work in the fast-paced healthcare environment, were identified as major barriers. Although the need for strong executive leadership was emphasized, "multi-system action" is needed for effective partnerships. Conclusion: Common approaches to research and knowledge translation are often not appropriate for addressing issues of health service design and health services organization. Nor is the research community providing expertise to many important activities that the healthcare system is taking to improve health services. A radical rethinking of how we prepare health service researchers; position research within the health system; and fund research activities and infrastructure is needed if the potential benefits of research are to be achieved. Lack of response to health system needs may contribute to research and ‘evidence-informed’ practice being further marginalized from healthcare operations. Interventions to address barriers must respond to the perspectives and experience of health leadership.</jats:p

Evidence of commitment to research partnerships? Results of two web reviews

Abstract Background Partnerships between academic researchers and health system leadership are often promoted by health research funding agencies as an important strategy in helping ensure that funded research is relevant and the results used. While potential benefits of such partnerships have been identified, there is limited guidance in the scientific literature for either healthcare organisations or researchers on how to select, build and manage effective research partnerships. Our main research objective was to explore the health system perspective on partnerships with researchers with a focus on issues related to the design and organisation of the health system and services. Two structured web reviews were conducted as one component of this larger study. Methods Two separate structured web reviews were conducted using structured data extraction tools. The first review focused on sites of health research bodies and those providing information on health system management and knowledge translation (n = 38) to identify what guidance to support partnerships might be available on websites commonly accessed by health leaders and researchers. The second reviewed sites from all health ‘regions’ in Canada (n = 64) to determine what criteria and standards were currently used in guiding decisions to engage in research partnerships; phone follow-up ensured all relevant information was collected. Results Absence of guidance on partnerships between research institutions and health system leaders was found. In the first review, absence of guidance on research partnerships and knowledge coproduction was striking and in contrast with coverage of other forms of collaboration such as patient/community engagement. In the second review, little evidence of criteria and standards regarding research partnerships was found. Difficulties in finding appropriate contact information for those responsible for research and obtaining a response were commonly experienced. Conclusion Guidance related to health system partnerships with academic researchers is lacking on websites that should promote and support such collaborations. Health region websites provide little evidence of partnership criteria and often do not make contact information to research leaders within health systems readily available; this may hinder partnership development between health systems and academia