A Nrf2-OSGIN1&2-HSP70 axis mediates cigarette smoke-induced endothelial detachment: implications for plaque erosion.

AIMS: Endothelial erosion of plaques is responsible for ∼30% of acute coronary syndromes (ACS). Smoking is a risk factor for plaque erosion, which most frequently occurs on the upstream surface of plaques where the endothelium experiences elevated shear stress. We sought to recreate these conditions in vitro to identify potential pathological mechanisms that might be of relevance to plaque erosion. METHODS AND RESULTS: Culturing human coronary artery endothelial cells (HCAECs) under elevated flow (shear stress of 7.5 Pa) and chronically exposing them to cigarette smoke extract (CSE) and tumour necrosis factor-alpha (TNFα) recapitulated a defect in HCAEC adhesion, which corresponded with augmented Nrf2-regulated gene expression. Pharmacological activation or adenoviral overexpression of Nrf2 triggered endothelial detachment, identifying Nrf2 as a mediator of endothelial detachment. Growth/Differentiation Factor-15 (GDF15) expression was elevated in this model, with protein expression elevated in the plasma of patients experiencing plaque erosion compared with plaque rupture. The expression of two Nrf2-regulated genes, OSGIN1 and OSGIN2, was increased by CSE and TNFα under elevated flow and was also elevated in the aortas of mice exposed to cigarette smoke in vivo. Knockdown of OSGIN1&2 inhibited Nrf2-induced cell detachment. Overexpression of OSGIN1&2 induced endothelial detachment and resulted in cell cycle arrest, induction of senescence, loss of focal adhesions and actin stress fibres, and disturbed proteostasis mediated in part by HSP70, restoration of which reduced HCAEC detachment. In ACS patients who smoked, blood concentrations of HSP70 were elevated in plaque erosion compared with plaque rupture. CONCLUSION: We identified a novel Nrf2-OSGIN1&2-HSP70 axis that regulates endothelial adhesion, elevated GDF15 and HSP70 as biomarkers for plaque erosion in patients who smoke, and two therapeutic targets that offer the potential for reducing the risk of plaque erosion.

Medical students' experience of the hidden curriculum around primary care careers: a qualitative exploration of reflective diaries.

OBJECTIVES: Primary healthcare internationally is facing a workforce crisis with fewer junior doctors choosing general practice (GP) as a career. In the UK, a national report on GP careers highlighted adverse influences during medical school on students' career choices. The authors explored these influences in two urban UK medical schools, both with relatively low numbers of students entering GP training. DESIGN: Using a phenomenological approach, the authors thematically analysed the reflective diaries of four medical students who were recruited as 'participant researchers' over a period of 10 months. These students made regular reflexive notes about their experiences related to GP career perceptions in their academic and personal environments, aiming to capture both positive and negative perceptions of GP careers. The research team discussed emerging data and iteratively explored and developed themes. SETTING: Two UK medical schools PARTICIPANTS: Undergraduate medical students RESULTS: Seven key themes were identified: the lack of visibility and physicality of GP work, the lack of aspirational GP role models, students' perceptions of a GP career as default, the performativity of student career choice with the perceptions of success linked to specialism, societal perceptions of GP careers, gender stereotyping of career choices and the student perception of life as a GP. CONCLUSIONS: Students overwhelmingly reflected on negative cues to GP careers, particularly through their experience of the hidden curriculum. Three recommendations are made: the need for increased representation of GP role models in clinical curricula content delivery and senior leadership; ensuring GP clerkships involve an active and authentic student role with patients, enabling students to experience GP's 'work' including managing complexity, uncertainty and risk. Finally, institutions need to consider students' experiences of the hidden curriculum and the effect this can have on students' perception of careers, alongside the challenges of rankings and perceived hierarchical positioning of disciplines.