Novel Role for the AnxA1-Fpr2/ALX Signaling Axis as a Key Regulator of Platelet Function to Promote Resolution of Inflammation

Background: Ischemia reperfusion injury (I/RI) is a common complication of cardiovascular diseases. Resolution of detrimental I/RI-generated prothrombotic and proinflammatory responses is essential to restore homeostasis. Platelets play a crucial part in the integration of thrombosis and inflammation. Their role as participants in the resolution of thromboinflammation is underappreciated; therefore we used pharmacological and genetic approaches, coupled with murine and clinical samples, to uncover key concepts underlying this role. Methods: Middle cerebral artery occlusion with reperfusion was performed in wild-type or annexin A1 (AnxA1) knockout (AnxA1-/-) mice. Fluorescence intravital microscopy was used to visualize cellular trafficking and to monitor light/dye-induced thrombosis. The mice were treated with vehicle, AnxA1 (3.3 mg/kg), WRW4 (1.8 mg/kg), or all 3, and the effect of AnxA1 was determined in vivo and in vitro. Results: Intravital microscopy revealed heightened platelet adherence and aggregate formation post I/RI, which were further exacerbated in AnxA1-/- mice. AnxA1 administration regulated platelet function directly (eg, via reducing thromboxane B2 and modulating phosphatidylserine expression) to promote cerebral protection post-I/RI and act as an effective preventative strategy for stroke by reducing platelet activation, aggregate formation, and cerebral thrombosis, a prerequisite for ischemic stroke. To translate these findings into a clinical setting, we show that AnxA1 plasma levels are reduced in human and murine stroke and that AnxA1 is able to act on human platelets, suppressing classic thrombin-induced inside-out signaling events (eg, Akt activation, intracellular calcium release, and Ras-associated protein 1 [Rap1] expression) to decrease IIbβ3 activation without altering its surface expression. AnxA1 also selectively modifies cell surface determinants (eg, phosphatidylserine) to promote platelet phagocytosis by neutrophils, thereby driving active resolution. (n=5-13 mice/group or 7-10 humans/group.) Conclusions: AnxA1 affords protection by altering the platelet phenotype in cerebral I/RI from propathogenic to regulatory and reducing the propensity for platelets to aggregate and cause thrombosis by affecting integrin (IIbβ3) activation, a previously unknown phenomenon. Thus, our data reveal a novel multifaceted role for AnxA1 to act both as a therapeutic and a prophylactic drug via its ability to promote endogenous proresolving, antithromboinflammatory circuits in cerebral I/RI. Collectively, these results further advance our knowledge and understanding in the field of platelet and resolution biology.Fil: Senchenkova, Elena Y.. State University of Louisiana; Estados UnidosFil: Ansari, Junaid. State University of Louisiana; Estados UnidosFil: Becker, Felix. University Hospital Muenster; AlemaniaFil: Vital, Shantel A.. State University of Louisiana; Estados UnidosFil: Al-Yafeai, Zaki. State University of Louisiana; Estados UnidosFil: Sparkenbaugh, Erica M.. University North Carolina Chapel Hill; Estados UnidosFil: Pawlinski, Rafal. University North Carolina Chapel Hill; Estados UnidosFil: Stokes, Karen Y.. State University of Louisiana; Estados UnidosFil: Carroll, Jennifer L.. State University of Louisiana; Estados UnidosFil: Dragoi, Ana-Maria. State University of Louisiana; Estados UnidosFil: Qin, Cheng Xue. Baker Heart And Diabetes Institute; AustraliaFil: Ritchie, Rebecca H.. Baker Heart And Diabetes Institute; AustraliaFil: Sun, Hai. University Hospital Muenster; AlemaniaFil: Cuellar-Saenz, Hugo H.. State University of Louisiana; Estados UnidosFil: Rubinstein Guichon, Mara Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina. Columbia University; Estados UnidosFil: Han, Yiping W.. Columbia University; Estados UnidosFil: Orr, A. Wayne. University Hospital Muenster; AlemaniaFil: Perretti, Mauro. Queen Mary University Of London; Reino UnidoFil: Granger, D. Neil. State University of Louisiana; Estados UnidosFil: Gavins, Felicity N.E.. State University of Louisiana; Estados Unido

Saudi Consensus Recommendations on the Management of Multiple Sclerosis: Family Planning within the Management of MS

This review article addresses the complex issues faced by individuals with Multiple Sclerosis (MS) who are planning a family, becoming pregnant, or wishing to breastfeed their baby. Recommendations and guidelines were discussed and agreed upon by neurologists, neuroradiologists, nurses, and pharmacists involved in the management of MS in the Kingdom of Saudi Arabia (KSA). MS itself does not harm a pregnancy, and people with MS of childbearing age can be encouraged to enjoy family life. Family planning should be a part of the initial conversation with a newly diagnosed patient of childbearing age. Interferons and glatiramer acetate can be continued throughout pregnancy and can be administered during breastfeeding if the benefits outweigh the risks. These DMTs may be considered for a woman with well-controlled MS who is planning a pregnancy or otherwise not using contraception, according to an individualized risk-benefit analysis. The use of contraception should be maintained during the administration of other disease-modifying therapies (DMTs). Natalizumab can be administered at a reduced administration frequency to women with high MS disease activity up to 30 weeks gestation (this agent may induce hematological abnormalities in the fetus). Other DMTs should be withdrawn for variable periods before contraception is stopped and immediately after the discovery of a pregnancy (beware of rebound disease activity after withdrawing natalizumab or fingolimod). Resumption of treatment should not be delayed in women at risk of relapse during the postpartum period and especially in those who do not wish to breastfeed

Saudi Consensus Recommendations on the Management of Multiple Sclerosis: Symptom Management and Vaccination

This article deals with recommendations on the management of symptoms of MS and on the provision of vaccinations in patients receiving disease-modifying therapies (DMTs). Symptoms of MS, such as fatigue, depression, urinary symptoms, spasticity, impairment of gait, and sexual dysfunction, are common in this population. Recognizing and addressing these symptoms is key to maintaining the quality of life of people with MS. Vaccination status should be reviewed and updated prior to initiation of DMTs. In general, vaccination should be avoided for variable periods after the initiation of some DMTs. Live attenuated vaccines are contraindicated and should be considered on a case-by-case basis. These consensus recommendations will present the best practices for vaccination in Saudi Arabia before, during, and after the COVID-19 pandemic. The recommendations will be updated periodically and as needed as new evidence becomes available

Saudi Consensus Recommendations on the Management of Multiple Sclerosis: Disease-Modifying Therapies and Management of Relapses

For the past 10 years, disease-modifying therapy (DMT) options for multiple sclerosis (MS) have grown remarkably where DMTs have been shown to reduce the risk of MS relapses. MS patients are advised to begin treatment with a DMT shortly after diagnosis to limit the possibility of disease progression over time. While patients with radiologically isolated syndrome do not require pharmacologic treatment, high-risk patients with clinically isolated syndrome are advised to start DMTs. This article provides evidence-based recommendations for DMT use in MS management, helping healthcare practitioners advise patients on treatment decisions. We aim to provide recommendations for the management of acute MS relapses. The recommendations herein were developed following the gathering of a panel of experts after evaluating international guidelines, and the latest evidence was collected through a comprehensive literature review

Saudi Consensus Recommendations on the Management of Multiple Sclerosis: Disease-Modifying Therapies and Management of Relapses

For the past 10 years, disease-modifying therapy (DMT) options for multiple sclerosis (MS) have grown remarkably where DMTs have been shown to reduce the risk of MS relapses. MS patients are advised to begin treatment with a DMT shortly after diagnosis to limit the possibility of disease progression over time. While patients with radiologically isolated syndrome do not require pharmacologic treatment, high-risk patients with clinically isolated syndrome are advised to start DMTs. This article provides evidence-based recommendations for DMT use in MS management, helping healthcare practitioners advise patients on treatment decisions. We aim to provide recommendations for the management of acute MS relapses. The recommendations herein were developed following the gathering of a panel of experts after evaluating international guidelines, and the latest evidence was collected through a comprehensive literature review

Decreased bioavailability of hydrogen sulfide links vascular endothelium and atrial remodeling in atrial fibrillation

Oxidative stress drives the pathogenesis of atrial fibrillation (AF), the most common arrhythmia. In the cardiovascular system, cystathionine γ-lyase (CSE) serves as the primary enzyme producing hydrogen sulfide (HS), a mammalian gasotransmitter that reduces oxidative stress. Using a case control study design in patients with and without AF and a mouse model of CSE knockout (CSE-KO), we evaluated the role of HS in the etiology of AF. Patients with AF (n = 51) had significantly reduced plasma acid labile sulfide levels compared to patients without AF (n = 65). In addition, patients with persistent AF (n = 25) showed lower plasma free sulfide levels compared to patients with paroxysmal AF (n = 26). Consistent with an important role for HS in AF, CSE-KO mice had decreased atrial sulfide levels, increased atrial superoxide levels, and enhanced propensity for induced persistent AF compared to wild type (WT) mice. Rescuing HS signaling in CSE-KO mice by Diallyl trisulfide (DATS) supplementation or reconstitution with endothelial cell specific CSE over-expression significantly reduced atrial superoxide, increased sulfide levels, and lowered AF inducibility. Lastly, low HS levels in CSE KO mice was associated with atrial electrical remodeling including longer effective refractory periods, slower conduction velocity, increased myocyte calcium sparks, and increased myocyte action potential duration that were reversed by DATS supplementation or endothelial CSE overexpression. Our findings demonstrate an important role of CSE and HS bioavailability in regulating electrical remodeling and susceptibility to AF