RESUMEN
BACKGROUND AND AIMS: Dysregulated cholesterol metabolism is a hallmark of atherosclerotic cardiovascular diseases, yet our understanding of how endogenous cholesterol synthesis affects atherosclerosis is not clear. The energy sensor AMP-activated protein kinase (AMPK) phosphorylates and inhibits the rate-limiting enzyme in the mevalonate pathway HMG-CoA reductase (HMGCR). Recent work demonstrated that when AMPK-HMGCR signaling was compromised in an Apoe-/- model of hypercholesterolemia, atherosclerosis was exacerbated due to elevated hematopoietic stem and progenitor cell mobilization and myelopoiesis. We sought to validate the significance of the AMPK-HMGCR signaling axis in atherosclerosis using a non-germline hypercholesterolemia model with functional ApoE. METHODS: Male and female HMGCR S871A knock-in (KI) mice and wild-type (WT) littermate controls were made atherosclerotic by intravenous injection of a gain-of-function Pcsk9D374Y-adeno-associated virus followed by high-fat and high-cholesterol atherogenic western diet feeding for 16 weeks. RESULTS: AMPK activation suppressed endogenous cholesterol synthesis in primary bone marrow-derived macrophages from WT but not HMGCR KI mice, without changing other parameters of cholesterol regulation. Atherosclerotic plaque area was unchanged between WT and HMGCR KI mice, independent of sex. Correspondingly, there were no phenotypic differences observed in hematopoietic progenitors or differentiated immune cells in the bone marrow, blood, or spleen, and no significant changes in systemic markers of inflammation. When lethally irradiated female mice were transplanted with KI bone marrow, there was similar plaque content relative to WT. CONCLUSIONS: Given previous work, our study demonstrates the importance of preclinical atherosclerosis model comparison and brings into question the importance of AMPK-mediated control of cholesterol synthesis in atherosclerosis.
RESUMEN
During a clinical lecturer role, parallel clinical and academic training is undertaken. The anticipation is that a lectureship represents an exciting and expansive time. However, a national crisis has been declared at the clinical lecturer level with a leaky pipeline of clinical academics resulting in dwindling numbers. Clinical lecturers are infrequently represented as a group partly due to their distributed nature and diverse job plans. We conducted a survey of clinical lecturers in the UK. Responses (n = 107) revealed a motivated but divided workforce. A content analysis revealed core elements that sculpt an individual's success or failure, but these were variably present. COVID-19 had a negative effect on many with various strategies reported to try and reset academic trajectories. Feelings of isolation and anxiety about a viable future in academia were significant findings. This echoes calls for a greater number of secure longer-term grants to ensure that clinical academics and their skills are retained within the research workforce. A continued effort to analytically appraise whether supportive elements are in place for all lecturers will help focus initiatives to foster excellence in clinical academic training for everyone.
