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Objective: Alterations in extracellular matrix quantity and composition contribute to atherosclerosis, with remodeling of the subendothelial basement membrane to a fibronectin-rich matrix preceding lesion development. Endothelial cell interactions with fibronectin prime inflammatory responses to a variety of atherogenic stimuli; however, the mechanisms regulating early atherogenic fibronectin accumulation remain unknown. We previously demonstrated that oxidized LDL (oxLDL) promotes endothelial pro inflammatory gene expression by activating the integrin α5β1, a classic mediator of fibronectin fibrillogenesis. Approach and Results: We now show that oxLDL drives robust endothelial fibronectin deposition and inhibiting α5β1 (blocking antibodies, α5 knockout cells) completely inhibits oxLDL-induced fibronectin deposition. Consistent with this, inducible endothelial-specific α5 integrin deletion in ApoE knockout mice significantly reduces atherosclerotic plaque formation, associated with reduced early atherogenic inflammation. Unlike TGFβ-induced fibronectin deposition, oxLDL does not induce fibronectin expression (mRNA, protein) or the endothelial-to-mesenchymal transition phenotype. In addition, we show that cell-derived and plasma-derived fibronectin differentially affect endothelial function, with only cell-derived fibronectin capable of supporting oxLDL-induced VCAM-1 expression despite plasma fibronectin deposition by oxLDL. The inclusion of EIIIA and EIIIB domains in cell-derived fibronectin mediates this effect, as EIIIA/EIIIB knockout endothelial cells show diminished oxLDL-induced inflammation. Furthermore, our data suggests that EIIIA/EIIIB-positive cellular fibronectin is required for maximal α5β1 recruitment to focal adhesions and fibronectin fibrillogenesis. Conclusions: Taken together, our data demonstrate that endothelial α5 integrins drives oxLDL-induced fibronectin deposition and early atherogenic inflammation. Additionally, we show that α5β1-dependent endothelial fibronectin deposition mediates oxLDL-dependent endothelial inflammation and fibronectin fibrillogenesis.

Neutrophils plays a crucial role in the intertwined processes of thrombosis and inflammation. Altered neutrophil phenotype may contribute to inadequate resolution which is known to be a major pathophysiological contributor of thrombo-inflammatory conditions such as Sickle Cell Disease (SCD). The endogenous protein Annexin A1 (AnxA1) facilitates inflammation resolution via Formyl Peptide Receptors (FPRs). We sought to comprehensively elucidate the functional significance of targeting neutrophil dependent AnxA1/FPR2/ALX pathway in SCD. Administration of AnxA1 mimetic peptide AnxA1Ac2-26 ameliorated cerebral thrombotic responses in Sickle transgenic mice via regulation of FPR2/ALX (a fundamental receptor involved in resolution) pathway. We demonstrated direct evidence that neutrophils with SCD phenotype play a key role in contributing to thrombo-inflammation. In addition, AnxA1Ac2-26 regulated activated SCD neutrophils through protein kinase B (Akt) and extracellular signal-regulated kinases (ERK1/2) to enable resolution. Herein, we present compelling conceptual evidence that targeting the AnxA1/FPR2/ALX pathway may provide new therapeutic possibilities against thrombo-inflammatory conditions such as SCD.

Objective- Flow patterns differentially regulate endothelial cell phenotype, with laminar flow promoting vasodilation and disturbed flow promoting endothelial proinflammatory activation. CSE (cystathionine γ-lyase), a major source of hydrogen sulfide (HS) in endothelial cells, critically regulates cardiovascular function, by both promoting vasodilation and reducing endothelial activation. Therefore, we sought to investigate the role of CSE in the endothelial response to flow. Approach and Results- Wild-type C57Bl/6J and CSE knockout ( CSE) mice underwent partial carotid ligation to induce disturbed flow in the left carotid. In addition, endothelial cells isolated from wild-type and CSE mice were exposed to either laminar or oscillatory flow, an in vitro model of disturbed flow. Interestingly, laminar flow significantly reduced CSE expression in vitro, and only disturbed flow regions show discernable CSE protein expression in vivo, correlating with enhanced HS production in wild-type C57BL/6J but not CSE mice. Lack of CSE limited disturbed flow-induced proinflammatory gene expression (ICAM-1[intercellular adhesion molecule 1], VCAM-1 [vascular cell adhesion molecular 1]) and monocyte infiltration and CSE endothelial cells showed reduced NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activation and proinflammatory gene expression in response to oscillatory flow in vitro. In addition, CSE mice showed reduced inward remodeling after partial carotid ligation. CSE mice showed elevated vascular nitrite levels (measure of nitric oxide [NO]) in the unligated carotids, suggesting an elevation in baseline NO production, and the NO scavenger 2-(4-carboxyphenyl)-4,5-dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxy-3-oxide normalized the reduced inward remodeling, but not inflammation, of ligated carotids in CSE mice. Conclusions- CSE expression in disturbed flow regions critically regulates both endothelial activation and flow-dependent vascular remodeling, in part through altered NO availability.

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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 (H 2 S), 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 H 2 S 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 H 2 S 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 H 2 S 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 H 2 S 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 H 2 S bioavailability in regulating electrical remodeling and susceptibility to AF.

In this report, we examine the case of a patient who developed antineutrophil cytoplasmic antibody (ANCA)associated vasculitis after receiving the Pfizer-BioNTech coronavirus disease 2019 (COVID-19) vaccine. This is a case of a 62-year-old female who received the first dose of COVID-19 vaccine in July 2021 before presenting a few weeks later with migrating polyarthralgia and hemoptysis. Autoimmune workup was positive for ANCA against proteinase 3 (PR3).

Aims Multiple myeloma accounts for over 10–15% of haematological malignancies. Continued molecular advances have resulted in the development of new drugs for treatment of multiple myeloma. Four drugs were approved by the Food and Drug Administration (FDA) in 2015, but their safety is not well defined. The aim of this study is to delineate the cardiovascular adverse events of these drugs. Methods We reviewed the adverse cardiac events of newly approved FDA drugs since 2015 using the US FDA Adverse Events Reporting System (FAERS) database. We calculated the reporting odds ratio (ROR) with 95% confidence interval (CIs) for the drugs that have the highest incidence of cardiovascular adverse events. Results Among the medications that have approved for multiple myeloma between 2015 and 2020, 4 novel drugs showed the highest incidence of cardiotoxicity. ROR (95% CI) for atrial fibrillation due to elotuzumab, ixazomib, daratumumab and panobinostat compared to other FAERS drugs was 5.8 (4.4–7.7), 1.9 (1.5–2.3), 4.8 (4.2–5.6) and 5.7 (4.1–8.1), respectively. The ROR (95% CI) for cardiac failure was 8.2 (6.4–10.5), 4.7 (4.1–5.4), 5.8 (4.9–6.7) and 5.6 (3.8–8.1) and ROR (95% CI) for coronary disease was 2.7 (1.9–3.9), 2.7 (2.3–3.2), 2.3 (1.9–2.8) and 4.6 (3.2–6.6) due to elotuzumab, ixazomib, daratumumab and panobinostat compared to all other drugs in FAERS. Conclusion Our results demonstrated that certain newly approved antimyeloma therapies are significantly associated with previously unknown cardiotoxicity. These results warrant further studies and highlight the importance of considering the cardiac history of patients with multiple myeloma when utilizing these novel agents.