Resveratrol Promotes Angiogenesis in a FoxO1-Dependent Manner in Hind Limb Ischemia in Mice.

Critical limb ischemia (CLI) is a severe form of peripheral artery diseases (PAD) and seriously endangers the health of people. Therapeutic angiogenesis represents an important treatment strategy for CLI; various methods have been applied to enhance collateral circulation. However, the current development drug therapy to promote angiogenesis is limited. Resveratrol (RSV), a polyphenol compound extracted from plants, has various properties such as anti-oxidative, anti-inflammatory and anti-cancer effects. Whether RSV exerts protective effects on CLI remains elusive. In the current study, we demonstrated that oral intake of RSV significantly improved hind limb ischemia in mice, and increased the expression of phosphorylated Forkhead box class-O1 (FoxO1). RSV treatment in human umbilical vein endothelial cells (HUVECs) could increase the phosphorylation of FoxO1 and its cytoplasmic re-localization to promote angiogenesis. Then we manipulated FoxO1 in HUVECs to further verify that the effect of RSV on angiogenesis is in a FoxO1-dependent manner. Furthermore, we performed metabolomics to screen the metabolic pathways altered upon RSV intervention. We found that the pathways of pyrimidine metabolism, purine metabolism, as well as alanine, aspartate and glutamate metabolism, were highly correlated with the beneficial effects of RSV on the ischemic muscle. This study provides a novel direction for the medical therapy to CLI.

Single Intraosseous Simvastatin Application Induces Endothelial Progenitor Cell Mobilization and Therapeutic Angiogenesis in a Diabetic Hindlimb Ischemia Rat Model.

BACKGROUND: Endothelial progenitor cells have shown the ability to enhance neovascularization. In this study, the authors tested whether intraosseous delivery of simvastatin could mobilize endothelial progenitor cells and enhance recovery in a hindlimb ischemia model. METHODS: There are eight groups of rats in this study: normal control; type 1 diabetes mellitus control group control without drug intervention; and type 1 diabetes mellitus rats that randomly received intraosseous simvastatin (0, 0.5, or 1 mg) or oral simvastatin administration (0, 20, or 400 mg). All type 1 diabetes mellitus rats had induced hindlimb ischemia. The number of endothelial progenitor cells in peripheral blood, and serum markers, were detected. The recovery of blood flow at 21 days after treatment was used as the main outcome. RESULTS: The authors demonstrated that endothelial progenitor cell mobilization was increased in the simvastatin 0.5- and 1-mg groups compared with the type 1 diabetes mellitus control and simvastatin 0-mg groups at 1, 2, and 3 weeks. Serum vascular endothelial growth factor levels were significantly increased at 2 weeks in the simvastatin 0.5- and 1-mg groups, in addition to the increase of the blood flow and the gastrocnemius weight at 3 weeks. Similar increase can also been seen in simvastatin 400 mg orally but not in simvastatin 20 mg orally. CONCLUSION: These findings demonstrate that a single intraosseous administration of simvastatin mobilized endothelial progenitor cells at a dose one-hundredth of the required daily oral dose in rats, and this potent mobilization of endothelial progenitor cells markedly improved diabetic limb ischemia by means of neovascularization.

Molecular basis of the effect of atorvastatin pretreatment on stem cell therapy in chronic ischemic diseases - critical limb ischemia.

Autologous stem cell therapy is the most promising alternative treatment in patients with chronic ischemic diseases, including ischemic heart disease and critical limb ischemia, which are characterized by poor prognosis related to serious impair of quality of life, high risk of cardiovascular events and mortality rates. However, one of the most serious shortcomings of stem cell transplantation are low survival after transplantation to the site of injury, as large number of stem cells are lost within 24 hours after delivery. Multiple studies suggest that combination of lipid-lowering drugs, statins, and stem cell transplantation might improve therapeutic efficacy in regenerative medicine. Statins are inhibitors of HMG-CoA reductase and belong to recommended therapy in all patients suffering from critical limb ischemia. Statins possess non-lipid effects which involve improvement of endothelial function, decrease of vascular inflammation and oxidative stress, anti-cancer and stem cell modulation capacities. These non-lipid effects are explained by inhibition of mevalonate synthesis via blocking isoprenoid intermediates synthesis, such as farnesylpyrophospate and geranylgeranylpyrophospate and result in modulation of the PI3K/Akt pathway. Moreover, statin-mediated microRNA regulation may contribute to the pleiotropic functions. MicroRNA interplay in gene regulatory network of IGF/Akt pathway may be of special significance for the treatment of critical limb ischemia. We assume further studies are needed for detailed analysis of statin interactions with microRNA at the molecular level and their link to PI3K/Akt and IGF/Akt pathway in stem cells, which are currently the most promising treatment strategy used in chronic ischemic diseases.

Effects of PCSK9 Inhibitor on Favorable Limb Outcomes in Patients with Chronic Limb-Threatening Ischemia.

AIM: The aim of this study was to examine the effects of evolocumab on favorable limb events in patients with chronic limb-threatening ischemia (CLTI). METHODS: A single-center, prospective observational study was performed on 30 patients with CLTI. The subjects were divided into 2 groups based on evolocumab administration: evolocumab-treated (E) group ( n=14) and evolocumab non-treated (non-E) group (n=16). The primary outcome was 12-month freedom from major amputation. The secondary outcomes were 12-month amputation-free survival (AFS), overall survival (OS), and wound-free limb salvage. The mean follow-up period was 18±11 months. RESULTS: No significant difference was detected between the two groups for the 12-month freedom from major amputation (log-rank p=0.15), while the 12-month AFS rate was significantly higher in the E group than that in the non-E group (log-rank p=0.02). The 12-month OS rate in the E group was shown a tendency for improvement, as compared with that in the non-E group (log-rank p=0.056). Evolocumab administration was not associated with a significant change in freedom from major amputation (HR, 0.23, 95% CI, 0.03-2.07, p=0.19). However, evolocumab administration was related to a tendency for improvement of AFS and OS (HR, 0.13, 95% CI, 0.02-1.06, p=0.056; HR, 0.16, 95% CI, 0.02-1.37, p=0.09, respectively). Moreover, The E group had a higher proportion of wound-free limb salvage at 12 months (92% vs. 42%, p=0.03). CONCLUSION: Evolocumab administration was associated with a better AFS outcome in patients with CLTI. Long-term administration of evolocumab over 12 months contributed to improving proportion of wound-free limb salvage.

Isquemia arterial aguda de membros superiores em pacientes diagnosticados com COVID-19: série de casos / Acute upper limb arterial ischemia in patients diagnosed with COVID-19: case series

Resumo A infecção pelo coronavírus 2 causador da síndrome respiratória aguda grave (SARS-CoV-2) em humanos foi detectada pela primeira vez em Wuhan, na China, em 2019 e dispersada mundialmente ao longo de 2020. As diferentes manifestações clínicas, com amplo espectro de apresentação, desde infecções assintomáticas até formas graves que podem levar a óbito, são desafiadoras. Este trabalho objetiva descrever uma série de quatro casos de isquemia arterial aguda dos membros superiores em pacientes diagnosticados com COVID-19, os quais foram manejados clinicamente com anticoagulação, antiagregação plaquetária e uso de prostanoides. Dois pacientes receberam alta hospitalar com regressão e delimitação da área isquêmica, sem necessidade de intervenção cirúrgica, e dois pacientes faleceram em decorrência de complicações pulmonares. Uma adequada compreensão da fisiopatologia dessa doença pode favorecer um melhor manejo clínico de suas complicações.

Abstract Infection by coronavirus 2, cause of the severe acute respiratory syndrome (SARS-CoV-2) in humans, was detected for the first time in Wuhan, China, in 2019, and spread globally over the course of 2020. Its different clinical manifestations are challenging, with a wide spectrum of presentations, ranging from asymptomatic infections to severe forms that can result in death. The objective of this study is to describe a series of four cases of acute arterial ischemia involving the upper limbs in patients diagnosed with COVID-19, which were managed clinically with anticoagulation, platelet antiaggregation, and prostanoids. Two patients were discharged from hospital with regression and delimitation of the ischemic zone, without needing surgical intervention, while two patients died from pulmonary complications. Adequate understanding of the pathophysiology of this disease could support better clinical management of its complications.

Alprostadil associated with low molecular weight heparin to treat limb ischemia caused by SARS-CoV2 / Alprostadil associado a heparina de baixo peso molecular para o tratamento da isquemia de membros causada por SARS-CoV2

Abstract The current coronavirus pandemic has already taken a great toll globally, causing massive morbidity and mortality. One of its severe forms is a thrombophilic state that can damage several systems. This article reports the case of 60-year-old female patient who presented with mild flu symptoms, which turned out to be a SARS-CoV2 infection, and ended up developing arterial thrombosis with limb ischemia in a private care hospital in Sorocaba, São Paulo, Brazil. Considering this progression, we decided to intervene with low molecular weight heparin and Alprostadil, achieving a good clinical outcome. Our description aims to identify key points and clinical signs that offer evidence of the therapeutic window and a treatment option for coagulatory presentations of COVID-19.

Resumo A atual pandemia de coronavírus já gerou danos profundos ao redor do mundo, causando grande quantidade de morbidades e mortes. Uma das manifestações das formas graves da doença é o estado trombofílico, que pode provocar danos em vários sistemas. Este artigo relata o caso de uma paciente do sexo feminino, 60 anos de idade, que foi internada em um serviço hospitalar privado com sintomas gripais inespecíficos leves, mas que progrediu com trombose arterial e isquemia de membros causada pelo SARS-CoV2. Devido à essa evolução, foi optada pela administração concomitante de heparina de baixo peso molecular e Alprostadil, com bom desfecho clínico. Nossa descrição objetiva identificar pontos-chave e sinais clínicos que evidenciem essa janela terapêutica, bem como uma opção de tratamento para as apresentações coagulatórias da COVID-19.