Autophagy as an emerging therapeutic target for age-related vascular pathologies.

Introduction: The incidence of age-related vascular diseases such as arterial stiffness, hypertension and atherosclerosis, is rising dramatically and is substantially impacting healthcare systems. Mounting evidence suggests that there is an important role for autophagy in maintaining (cardio)vascular health. Impaired vascular autophagy has been linked to arterial aging and the initiation of vascular disease.Areas covered: The function and implications of autophagy in vascular smooth muscle cells and endothelial cells are discussed in healthy blood vessels and arterial disease. Furthermore, we discuss current treatment options for vascular disease and their links with autophagy. A literature search was conducted in PubMed up to October 2019.Expert opinion: Although the therapeutic potential of inducing autophagy in age-related vascular pathologies is considerable, several issues should be addressed before autophagy induction can be clinically used to treat vascular disease. These issues include uncertainty regarding the most effective drug target as well as the lack of potency and selectivity of autophagy inducing drugs. Moreover, drug tolerance or autophagy mediated cell death have been reported as possible adverse effects. Special attention is required for determining the cause of autophagy deficiency to optimize the treatment strategy.

Evaluating the implementation fidelity of New Medicines Service for asthma patients in community pharmacies in Belgium.

BACKGROUND: In October 2013, a New Medicines Service (NMS) was introduced in community pharmacies in Belgium to support asthma patients who are novice users of inhaler devices with corticosteroids. The protocol-based intervention used the Asthma Control Test (ACT) and the Medication Adherence Report Scale (MARS) to assess asthma control and medication adherence. The NMS is the first initiative that puts advanced pharmaceutical care into practice in Belgium. The present study evaluated the degree to which the NMS program is delivered as intended, drawing on the concept of implementation fidelity (IF). METHODS: The main dimensions of IF and potential moderating and facilitating factors for the implementation of NMS in community pharmacies were evaluated using telephone interviews with pharmacists (n = 497), semi-structured interviews with patients eligible for NMS (n = 30), focus groups among general practitioners (n = 72) and lung specialists (n = 5), and a work system analysis in community pharmacies (n = 19). RESULTS: The uptake of NMS in Belgian community pharmacies remains low. In addition to practical barriers, pharmacists found it difficult to identify new asthmatic patients when they were not informed about the diagnosis. A lack of commitment from physicians, patients and pharmacists was noted in the early start-up phase of the program. Many pharmacists did not see how NMS differed from existing pharmaceutical care. Physicians considered this service as part of their own tasks and discouraged ACT for asthma follow-up in the community pharmacy. CONCLUSIONS: The introduction of the NMS program was not sufficiently embedded in the Belgian health care organization, causing low uptake and resistance to its implementation by pharmacists, patients, and other health care professionals. To increase the uptake of this type of service and its possible extension to other patient groups, more collaboration among the different health care professionals during design and implementation is necessary, as well as systematic data collection to monitor the quality of the service, better training of pharmacists, and more information for patients and physicians.

Intraplaque neovascularization as a novel therapeutic target in advanced atherosclerosis.

INTRODUCTION: Atherosclerosis is a lipid-driven inflammatory process with a tremendously high mortality due to acute cardiac events. There is an emerging need for new therapies to stabilize atherosclerotic lesions. Growing evidence suggests that intraplaque (IP) neovascularisation and IP hemorrhages are important contributors to plaque instability. AREAS COVERED: Neovascularization is a complex process that involves different growth factors and inflammatory mediators of which their individual significance in atherosclerosis remains poorly understood. This review discusses different aspects of IP neovascularization in atherosclerosis including the potential treatment opportunities to stabilize advanced plaques. Furthermore, we highlight the development of accurate and feasible in vivo imaging modalities for IP neovascularization to prevent acute events. EXPERT OPINION: Although lack of a valuable animal model of IP neovascularization impeded the investigation of a causal and straightforward link between neovascularization and atherosclerosis, recent evidence shows that vein grafts in ApoE*3 Leiden mice as well as plaques in ApoE(-/-) Fbn1(C1039G+/-) mice are useful models for intraplaque neovessel research. Even though interference with vascular endothelial growth factor (VEGF) signalling has been widely investigated, new therapeutic opportunities have emerged. Cell metabolism, in particular glycolysis and fatty acid oxidation, appears to perform a crucial role in the development of IP neovessels and thereby serves as a promising target.

Defective autophagy in vascular smooth muscle cells accelerates senescence and promotes neointima formation and atherogenesis.

Autophagy is triggered in vascular smooth muscle cells (VSMCs) of diseased arterial vessels. However, the role of VSMC autophagy in cardiovascular disease is poorly understood. Therefore, we investigated the effect of defective autophagy on VSMC survival and phenotype and its significance in the development of postinjury neointima formation and atherosclerosis. Tissue-specific deletion of the essential autophagy gene Atg7 in murine VSMCs (atg7-/- VSMCs) caused accumulation of SQSTM1/p62 and accelerated the development of stress-induced premature senescence as shown by cellular and nuclear hypertrophy, CDKN2A-RB-mediated G1 proliferative arrest and senescence-associated GLB1 activity. Transfection of SQSTM1-encoding plasmid DNA in Atg7+/+ VSMCs induced similar features, suggesting that accumulation of SQSTM1 promotes VSMC senescence. Interestingly, atg7-/- VSMCs were resistant to oxidative stress-induced cell death as compared to controls. This effect was attributed to nuclear translocation of the transcription factor NFE2L2 resulting in upregulation of several antioxidative enzymes. In vivo, defective VSMC autophagy led to upregulation of MMP9, TGFB and CXCL12 and promoted postinjury neointima formation and diet-induced atherogenesis. Lesions of VSMC-specific atg7 knockout mice were characterized by increased total collagen deposition, nuclear hypertrophy, CDKN2A upregulation, RB hypophosphorylation, and GLB1 activity, all features typical of cellular senescence. To conclude, autophagy is crucial for VSMC function, phenotype, and survival. Defective autophagy in VSMCs accelerates senescence and promotes ligation-induced neointima formation and diet-induced atherogenesis, implying that autophagy inhibition as therapeutic strategy in the treatment of neointimal stenosis and atherosclerosis would be unfavorable. Conversely, stimulation of autophagy could be a valuable new strategy in the treatment of arterial disease.