On the basis of Covid-19-induced pulmonary pathological and vascular changes, we hypothesize that the anti-vascular endothelial growth factor (VEGF) drug bevacizumab might be beneficial for treating Covid-19 patients. From Feb 15 to April 5, 2020, we conducted a single-arm trial (NCT04275414) and recruited 26 patients from 2-centers (China and Italy) with severe Covid-19, with respiratory rate ≥30 times/min, oxygen saturation ≤93% with ambient air, or partial arterial oxygen pressure to fraction of inspiration O2 ratio (PaO2/FiO2) >100 mmHg and ≤300 mmHg, and diffuse pneumonia confirmed by chest imaging. Followed up for 28 days. Among these, bevacizumab plus standard care markedly improves the PaO2/FiO2 ratios at days 1 and 7. By day 28, 24 (92%) patients show improvement in oxygen-support status, 17 (65%) patients are discharged, and none show worsen oxygen-support status nor die. Significant reduction of lesion areas/ratios are shown in chest computed tomography (CT) or X-ray within 7 days. Of 14 patients with fever, body temperature normalizes within 72 h in 13 (93%) patients. Relative to comparable controls, bevacizumab shows clinical efficacy by improving oxygenation and shortening oxygen-support duration. Our findings suggest bevacizumab plus standard care is highly beneficial for patients with severe Covid-19. Randomized controlled trial is warranted.

Brain-derived neurotrophic factor (BDNF) plays an important role in the activity-dependent regulation of synaptic structure and function via tropomyosin related kinase B (TrkB) receptor activation. However, whether BDNF could regulate TrkB levels at synapse during long-term potentiation (LTP) is still unknown. We show in cultured rat hippocampal neurons that chemical LTP (cLTP) stimuli selectively promote endocytic recycling of BDNF-dependent full-length TrkB (TrkB-FL) receptors, but not isoform T1 (TrkB.T1) receptors, via a Rab11-dependent pathway. Moreover, neuronal-activity-enhanced TrkB-FL recycling could facilitate receptor translocation to postsynaptic density and enhance BDNF-induced extracellular signal-regulated kinase and phosphatidylinositol 3-kinase activation and rat hippocampal neuron survival. Finally, we found that cLTP could stimulate the switch of Rab11 from an inactive to an active form and that GTP-bound Rab11 could enhance the interaction between TrkB-FL and PSD-95. Therefore, the recycling endosome could serve as a reserve pool to supply TrkB-FL receptors for LTP maintenance. These findings provide a mechanistic link between Rab11-dependent endocytic recycling and TrkB modulation of synaptic plasticity.

Rationale: The NLRP3 (NLR [NOD-like receptor] family, pyrin domain containing 3) inflammasome is an important driver of atherosclerosis. Our previous study shows that chaperone-mediated autophagy (CMA), one of the main lysosomal degradative process, has a regulatory role in lipid metabolism of macrophages. However, whether the NLRP3 inflammasome is regulated by CMA, and the role of CMA in atherosclerosis remains unclear. Objective: To determine the role of CMA in the regulation of NLRP3 inflammasome and atherosclerosis. Methods and Results: The expression of CMA marker, LAMP-2A (lysosome-associated membrane protein type 2A), was first analyzed in ApoE −/− mouse aortas and human coronary atherosclerotic plaques, and a significant downregulation of LAMP-2A in advanced atherosclerosis in both mice and humans was observed. To selectively block CMA, we generated macrophage-specific conditional LAMP-2A knockout mouse strains in C57BL/6 mice and ApoE −/− mice. Deletion of macrophage LAMP-2A accelerated atherosclerotic lesion formation in the aortic root and the whole aorta in ApoE −/− mice. Mechanistically, LAMP-2A deficiency promoted NLRP3 inflammasome activation and subsequent release of mature IL (interleukin)-1β in macrophages and atherosclerotic plaques. Furthermore, gain-of-function studies verified that restoration of LAMP-2A levels in LAMP-2A–deficient macrophages greatly attenuated NLRP3 inflammasome activation. Importantly, we identified the NLRP3 protein as a CMA substrate and demonstrated that LAMP-2A deficiency did not affect the NLRP3 mRNA levels but hindered degradation of the NLRP3 protein through CMA pathway. Conclusions: CMA function becomes impaired during the progression of atherosclerosis, which increases NLRP3 inflammasome activation and secretion of IL-1β, promoting vascular inflammation and atherosclerosis progression. Our study unveils a new mechanism by which NLRP3 inflammasome is regulated in macrophages and atherosclerosis, thus providing a new insight into the role of autophagy-lysosomal pathway in atherosclerosis. Pharmacological activation of CMA may provide a novel therapeutic strategy for atherosclerosis and other NLRP3 inflammasome/IL-1β–driven diseases.

Mirabegron (Myrbetriq) is a β3-adrenoreceptor agonist approved for treating overactive bladder syndrome in human patients. This drug can activate brown adipose tissue (BAT) in adult humans and rodents through the β3-adrenoreceptor-mediated sympathetic activation. However, the effect of the mirabegron, approved by the US Food and Drug Administration, on atherosclerosis-related cardiovascular disease is unknown. Here, we show that the clinical dose of mirabegron-induced BAT activation and browning of white adipose tissue (WAT) exacerbate atherosclerotic plaque development. In apolipoprotein E −/− (ApoE −/− ) and low-density lipoprotein (LDL) receptor −/− (Ldlr −/− ) mice, oral administration of clinically relevant doses of mirabegron markedly accelerates atherosclerotic plaque growth and instability by a mechanism of increasing plasma levels of both LDL-cholesterol and very LDL-cholesterol remnants. Stimulation of atherosclerotic plaque development by mirabegron is dependent on thermogenesis-triggered lipolysis. Genetic deletion of the critical thermogenesis-dependent protein, uncoupling protein 1, completely abrogates the mirabegron-induced atherosclerosis. Together, our findings suggest that mirabegron may trigger cardiovascular and cerebrovascular diseases in patients who suffer from atherosclerosis. mirabegron | atherosclerosis | plaque instability | lipolysis | adipose tissue A therosclerosis, the thickening, hardening, and loss of elasticity of the arterial vessel wall, is the major cause of morbidity and mortality worldwide (1-4). Atherosclerotic lesions containing fatty plaques, cholesterol, and inflammatory cells are the primary causes of cardiovascular disease and stroke (5, 6). Atherosclerosis as a chronic and progressive disease usually starts with damage of the endothelial layer of an artery. Hypertension, hyperglycemia, hyperlipidemia especially hypercholesterolemia, smoking, obesity and diabetes, certain inflammatory disorders such as arthritis, infections, and drugs are the common risk factors of atherosclerotic plaque formation (7,8). Of interest, high incidences of myocardial infarction and stroke have been associated with colder ambient temperature and cold seasons (9, 10). Although the exact mechanism underlying low ambient temperature has not been elucidated, our recent findings show that cold-induced lipolysis in brown adipose tissue (BAT) and browning of white adipose tissue (WAT) may partly explain the high incidences of cardiovascular disease and stroke (11).The balance between energy deposition and dissipation is regulated by multiple factors, including the central nervous system, the endocrine system, food intake, physical exercise, pathological disease, and medications (12,13). Although WAT stores excessive energy in its lipid form, activated BAT specializes energy consumption by producing heat (14,15). Under certain conditions such as cold exposure, WAT, especially that located in the s.c. region, undergoes the brown-like transition, a process named browning WAT (16,17). Instead of stor...