Garret A. FitzGerald

BACKGROUND Low-dose aspirin is widely used for the secondary prevention of cardiovascular disease. The beneficial effects of low-dose aspirin are attributable to its inhibition of platelet Cox (cyclooxygenase)-1–derived thromboxane A2. Until recently, the use of the Pf4 (platelet factor 4) Cre has been the only genetic approach to generating megakaryocyte/platelet ablation of Cox-1 in mice. However, Pf4-ΔCre displays ectopic expression outside the megakaryocyte/platelet lineage, especially during inflammation. The use of the Gp1ba (glycoprotein 1bα) Cre promises a more specific, targeted approach. METHODS To evaluate the role of Cox-1 in platelets, we crossed Pf4-ΔCre or Gp1ba-ΔCre mice with Cox-1flox/flox mice to generate platelet Cox-1−/− mice on normolipidemic and hyperlipidemic (Ldlr−/−) backgrounds. RESULTS Ex vivo platelet aggregation induced by arachidonic acid or adenosine …

Arachidonic acid is a polyunsaturated fatty acid con-stituent of cell membranes, mobilized for release by activation of phospholipases by diverse physical and chemical stimuli. Its transformation to unstable endoperoxide prostaglandins G2 and H2 is catalyzed by enzymes (PTGS-1 and 2) colloquially known as COXs (cyclooxygenases). These lipids, in turn, are transformed to prostaglandins and thromboxane by their respective synthases, expressed such that most cells make one or 2 dominant products. Deletion of the G protein receptors activated by prostaglandins and thromboxane has revealed a remarkably diverse and sometimes contrasting biology. 1 The biosynthetic enzymes and receptors in this pathway have proven to be fruitful drug targets. Thus, the clinical efficacy of low dose aspirin is explained by inhibition of platelet COX-1 derived TxA2 and the efficacy of drugs like other NSAIDS (and higher doses of …

Optimal lung repair and regeneration are essential for recovery from viral infections, including influenza A virus (IAV). We have previously demonstrated that acute inflammation and mortality induced by IAV is under circadian control. However, it is not known whether the influence of the circadian clock persists beyond the acute outcomes. Here, we utilize the UK Biobank to demonstrate an association between poor circadian rhythms and morbidity from lower respiratory tract infections, including the need for hospitalization and mortality after discharge; this persists even after adjusting for common confounding factors. Furthermore, we use a combination of lung organoid assays, single-cell RNA sequencing, and IAV infection in different models of clock disruption to investigate the role of the circadian clock in lung repair and regeneration. We show that lung organoids have a functional circadian clock and the disruption …

Prostanoids are biologically active lipids generated from arachidonic acid by the action of the COX (cyclooxygenase) isozymes. NSAIDs, which reduce the biosynthesis of prostanoids by inhibiting COX activity, are effective anti-inflammatory, antipyretic, and analgesic drugs. However, their use is limited by cardiovascular adverse effects, including myocardial infarction, stroke, hypertension, and heart failure. While it is well established that NSAIDs increase the risk of atherothrombotic events and hypertension by suppressing vasoprotective prostanoids, less is known about the link between NSAIDs and heart failure risk. Current evidence indicates that NSAIDs may increase the risk for heart failure by promoting adverse myocardial and vascular remodeling. Indeed, prostanoids play an important role in modulating structural and functional changes occurring in the myocardium and in the vasculature in response to …

High-density lipoprotein (HDL) nanoparticles promote endothelial cell (EC) function and suppress inflammation, but their utility in treating EC dysfunction has not been fully explored. Here, we describe a fusion protein named ApoA1-ApoM (A1M) consisting of apolipoprotein A1 (ApoA1), the principal structural protein of HDL that forms lipid nanoparticles, and ApoM, a chaperone for the bioactive lipid sphingosine 1-phosphate (S1P). A1M forms HDL-like particles, binds to S1P, and is signaling competent. Molecular dynamics simulations showed that the S1P-bound ApoM moiety in A1M efficiently activated EC surface receptors. Treatment of human umbilical vein ECs with A1M-S1P stimulated barrier function either alone or cooperatively with other barrier-enhancing molecules, including the stable prostacyclin analog iloprost, and suppressed cytokine-induced inflammation. A1M-S1P injection into mice during sterile …

Rationale Complement pathway hyperactivation may contribute to sepsis and SARS-CoV-2 sepsis (COVID-19) pathology, yet the relative specificity of circulating complement factors for COVID-19, and whether circulating complement features associate with sepsis severity, are unknown. We hypothesized that COVID-19 would manifest greater alternative pathway activation than non-COVID sepsis and that specific feature dysregulation would provide rationale for future therapeutic investigation. Methods We prospectively enrolled hospitalized participants with sepsis due to COVID-19 (n= 257) or non-COVID infections (n= 246) and collected plasma within 3 days of admission. We separately collected blood from ambulatory volunteers (‘controls’n= 326). We used multiplex ELISA to measure plasma complement protein abundance (C1q, C3, C4, C5, complement factors H and I (CFH, CFI) and markers of complement …

Chronic kidney disease (CKD) represents a significant global burden. Hypertension is a modifiable risk factor for rapid progression of CKD. We extend the risk stratification by introducing the non-parametric determination of rhythmic components in 24-h profiles of ambulatory blood pressure monitoring (ABPM) in the Chronic Renal Insufficiency Cohort (CRIC) and the African American Study for Kidney Disease and Hypertension (AASK) cohort using Cox proportional hazards models. We find that rhythmic profiling of BP through JTK_CYCLE analysis identifies subgroups of CRIC participants that were more likely to die due to cardiovascular causes. While our fully adjusted model shows a trend towards a significant association between absent cyclic components and cardiovascular death in the full CRIC cohort (HR: 1.71,95% CI: 0.99–2.97, p = 0.056), CRIC participants with a history of cardiovascular disease (CVD …

Longitudinal studies associate shiftwork with cardiometabolic disorders but do not establish causation or elucidate mechanisms of disease. We developed a mouse model based on shiftwork schedules to study circadian misalignment in both sexes. Behavioral and transcriptional rhythmicity were preserved in female mice despite exposure to misalignment. Females were protected from the cardiometabolic impact of circadian misalignment on a high-fat diet seen in males. The liver transcriptome and proteome revealed discordant pathway perturbations between the sexes. Tissue-level changes were accompanied by gut microbiome dysbiosis only in male mice, biasing toward increased potential for diabetogenic branched chain amino acid production. Antibiotic ablation of the gut microbiota diminished the impact of misalignment. In the United Kingdom Biobank, females showed stronger circadian rhythmicity in …