Exposure to fine particulate matter (PM2.5) air pollution is associated with an increased cardiometabolic disease risk. However, although exposure timing is recognized as an important toxicity determinant, the chronotoxicity of PM2.5 exposure is less explored. To evaluate whether PM2.5 sensitivity depends on exposure timing, adult male C57/BL6 mice were exposed to concentrated PM2.5 (CAP, 6 h/day, 30 days) either during the inactive (light) phase (Zeitgeber time, ZT1 to 7) or the active (dark) phase (ZT17 to 23). Metabolic health was assessed by measuring body weight, fasting blood glucose, and plasma insulin levels. Oxidative stress and inflammatory responses in aortas and lungs were examined by quantitative real-time (qRT)-PCR, and pulmonary and circulating redox changes were measured calorimetrically. Although CAP exposure during the active phase increased blood glucose levels, inactive-phase exposure more profoundly increased antioxidant enzyme and inflammatory mRNA abundance in lungs and aortas. Inactive-phase exposure also intensified pulmonary and systemic lipid peroxidation and increased the depletion of circulating nitric oxide and lung glutathione. Examining the ability to protect against CAP-induced pulmonary oxidative stress, we found that the pulmonary antioxidant enzyme mRNA expression showed circadian rhythmicity that peaked during the active phase. These data suggest that a superior pulmonary antioxidant defense potential during the active phase could contribute to the protection against the PM2.5-induced vascular and pulmonary effects but not its impact on glucose homeostasis. Our study identified that exposure sensitivity depends on the exposure timing, which is of significance as it informs on timely susceptibility windows that could help to mitigate PM2.5 toxicity.

BACKGROUND: After a myocardial infarction (MI), the heart remodels as surviving myocardium compensates for the loss of functional tissue and elevated ventricular wall stress. This post-MI remodeling is characterized by left ventricular (LV) dilation and ensuing cardiac dysfunction. Severe LV dilation is associated with poor patient outcomes—such as exercise intolerance—and often portends the development of symptomatic heart failure. Exercise, which prompts physiologic cardiac remodeling, presents a promising therapeutic strategy for mitigating this structural and functional decline. OBJECTIVE: The objective of this study is to determine the impact of exercise on the structural remodeling and functional decline caused by MI in female mice. Given that male and female hearts respond distinctly to the remodeling stimuli of MI and exercise, only female mice were included in the present study. We hypothesize that exercise attenuates cardiac dysfunction linked to post-MI LV dilation and promotes remodeling outcomes that are conducive to improvements to exercise capacity. METHODS AND RESULTS: Female C57BL/6J mice, 16 to 21 weeks of age, were subjected to non-reperfused occlusion of the left coronary artery to induce MI. Four days later, echocardiography was performed, and mice with LV ejection fraction under 40% were randomized to exercise (EXE; n=11) or sedentary (SED; n=13) groups the next day. EXE mice were given continuous access to voluntary exercise wheels. Echocardiography was repeated after five weeks of EXE or SED conditions. Mice performed treadmill running-based exercise capacity tests (ECTs) before MI and five weeks after MI. Five weeks after MI, female EXE mice had similar LV volumes compared to SED controls. EXE mice had greater atrial weights (p=0.0435) than SED mice; however, no differences in mid-LV wall thicknesses were observed on M-mode echocardiography. Voluntary post-MI exercise did not impact functional metrics of ejection fraction, stroke volume, and cardiac output at rest. Despite similar LV dysfunction, EXE mice had increased work capacity by the five-week ECT (p< 0.0001), with an average work output of 28 joules (J) compared to the SED group’s average of 4.8 J. CONCLUSIONS: Although voluntary running did not mitigate post-MI LV dilation in female mice, it enhanced exercise tolerance. Further studies will determine the relative contributions of peripheral skeletal muscle versus cardiopulmonary adaptations to this effect. Disclosure of funding sources: We acknowledge NIH support (P30 GM127607, S10 OD038345, and R01 HL163272), and the Jewish Heritage Fund for Excellence. The content is solely the responsibility of the authors and may not represent views of the funding agencies. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Organ function depends on communication among cell types to coordinate tissue growth and repair. Although fibroblasts are critical to this process, their role in regulating inflammatory responses to injury remain ambiguous. Here, we show that transforming growth factor β-activated kinase 1 (TAK1) is a gatekeeper of an inflammatory cardiac fibroblast phenotype. In cardiac fibroblasts, TAK1 signaling controls the acquisition of defining features of inflammatory fibroblasts, including chemokine and cytokine synthesis, lipid mediator production, metalloproteinase activity, and damage-associated molecular pattern recognition. Moreover, TAK1 propagates IL-1β and TNF-α signaling, but not TGF-β-SMAD signaling, regulating inflammatory programs by increasing chemokine secretion while decreasing lipid mediator production. Fibroblast-specific TAK1 deletion decreases neutrophil chemotaxis in vitro and immune cell recruitment after myocardial infarction in vivo, which is associated with improved cardiac remodeling and function in male mice. These results further resolve the nature and function of inflammatory fibroblasts in cardiac responses to injury and identify TAK1 signaling as a critical mediator.

Ambient particulate matter (PM2.5) exposure is a major environmental risk factor for cardiopulmonary disease, but its effects on erythroid homeostasis remain incompletely understood. Although prior in vitro work indicates that PM2.5 can damage circulating red blood cells (RBCs), whether exposure alters erythropoiesis and the coordinated clearance of senescent RBCs has not been fully explored. Using a mouse model of whole-body exposure to concentrated ambient PM2.5 (CAP), we investigated associations between inhaled PM on erythroid output, splenic macrophage function, and lipid mediator signaling. CAP exposure was associated with suppressed erythropoietin levels, reduced circulating reticulocytes, and decreased erythroid precursor populations in the bone marrow, consistent with impaired erythropoiesis. Despite preserved splenic architecture, CAP-exposed mice exhibited reduced splenic iron and heme content, consistent with diminished erythrocyte turnover and processing. Targeted lipidomic profiling revealed broad suppression of proresolving lipid mediators in the spleen, with lipoxin A4 (LXA4) among the most consistently reduced species. Expression of the LXA4 receptor, ALX/FPR2, was also downregulated with prolonged exposure. Importantly, removal of CAP and return to filtered air resulted in normalization of splenic lipid mediator profiles, restoration of LXA4 levels, and recovery of erythroid parameters, including reticulocyte abundance and RBC stress markers. Together, these findings suggest that altered resolution signaling contributes to PM2.5-induced disruption of erythroid homeostasis and implicate macrophage-lipid mediator pathways in the hematologic response to environmental stress.

BACKGROUND:Diet-induced white adipose tissue inflammation is associated with insulin resistance and metabolic perturbations. Conversely, exercise protects against the development of diet-induced chronic inflammation and insulin resistance independent of weight loss; however, the mechanisms remain largely unknown. We have recently shown that through adrenergic stimulation of macrophages, exercise promotes resolution of acute peritoneal inflammation by enhancing the biosynthesis of specialized proresolving lipid mediators. In this study, we sought to determine whether exercise stimulates proresolving pathways in adipose tissue and whether this response is modified by diet. Specifically, we hypothesized that exercise stimulates proresolving pathways by adrenergic signaling, which is inhibited by high-fat diet, priming the development of chronic inflammation in the adipose tissue. METHODS:To explore the dietary dependence of the proresolving effects of exercise, mice were fed either a control or high-fat diet for 2 weeks before, and throughout, a 4-week period of daily treadmill running. Glucose handling, body weight and composition, lipemia, and exercise performance were evaluated at the end of the feeding and exercise interventions. Likewise, changes in catecholamines and their biosynthetic enzymes were measured along with adipose tissue specialized proresolving lipid mediator levels and macrophage phenotype and abundance. RESULTS:When compared with sedentary controls, macrophages isolated from mice exposed to 4 weeks of exercise display elevated expression of the specialized proresolving lipid mediator biosynthetic enzyme Alox15, while adipose tissue specialized proresolving lipid mediator levels and anti-inflammatory CD301+ M2 macrophages increased. These changes were dependent upon diet as 6 weeks of feeding with high-fat diet abrogated the proresolving effect of exercise when compared with control diet-fed animals. Interestingly, exercise-induced epinephrine production was inhibited by high-fat diet, which diminished the expression of the epinephrine biosynthetic enzyme PNMT (phenylethanolamine N-methyltransferase) in adrenal glands. CONCLUSIONS:Taken together, these results suggest that a diet high in fat diminishes the proresolving effects of exercise in the adipose tissue via decreasing the biosynthesis of catecholamines.

Introduction: Cardiac fibroblasts, known for their reactivity to pro-inflammatory stimuli, are increasingly recognized as key mediators of inflammation. TGF-β activated kinase 1 (TAK1) has been identified to integrate diverse inflammatory signals, but its role in fibroblast biology and myocardial remodeling remains unclear. The goal of this study was to determine the role of fibroblast-TAK1 signaling on acquisition of an inflammatory phenotype and in post-myocardial infarction (MI) repair and remodeling. We hypothesize that TAK1 signaling integrates inflammatory signals to promote cardiac fibroblast activation, which regulates inflammation and remodeling after MI. Methods and Results: We used a fibroblast-specific model for TAK1 knockdown, i.e. Col1a2-Cre ERT TAK1 fl/fl mice, and littermate controls to determine how TAK1 influences remodeling after permanent coronary ligation. Deletion of TAK1 in fibroblasts in vivo prior to MI improved functional outcomes and reduced fibrosis 28 days post-MI in male mice (n=9-14/group; p<0.05). Interestingly, the female cohort experienced greater rates of mortality in TAK1 deleted mice (52.0% vs 22.7%; n=22-25/group). Flow cytometric evaluation of immune cells in the hearts showed that fibroblast-TAK1 deletion reduced CD45 pos leukocytes, neutrophils, and Ly6C low patrolling monocytes acutely post-MI (n=6-13/group; p<0.05). To determine how TAK1 may regulate the pro-inflammatory phenotype, isolated cardiac fibroblasts from TAK1 fl/fl mice were pretreated with Ad-CMV-iCre and stimulated with TGFβ, TNFα, or IL-1β. Notably, TAK1 deletion suppressed TNFα and IL-1β-dependent p-p38, p-JNK, and NFκB signaling (n=5/group; p<0.05). Bulk RNAseq analysis further revealed that TAK1 inhibition significantly reduced the expression of several inflammatory and stress response genes following IL-1β activation, many of which were also decreased at the protein level (MCP-1, RANTES, G-CSF, MMP3, iNOS; n=4/group, p<0.05). Lastly, LC-MS/MS evaluation of lipid mediators in conditioned medium showed that TAK1 deletion increases production of several resolvins (RvE2, RvD1, RvD4) and lipoxins (LXA 4 , 15( R )-LXA 4 ) (n=3/group; p<0.05). Conclusion: TAK1 signaling in cardiac fibroblasts is a critical regulator of inflammation and immune cell recruitment post-MI. Fibroblast-specific TAK1 suppression improves cardiac function and structure in male mice, likely by attenuating inflammatory signaling and promoting pro-resolving lipid mediator production. Notably, the differences in outcomes observed between males and females may be attributed to previously documented sex-specific variations in inflammatory responses. NIH R01 HL168198, NIH F30 HL165813, This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Physical activity and exercise confer health benefits through actions on several physiological systems; however, the mechanisms by which they impact renal health remain poorly understood. Studies show that exercise slows age-related decline in kidney function and protects against acute kidney injury (AKI). We hypothesize that exercise triggers adaptative responses, which preserve hemodynamic balance in the kidneys under stress. We evaluated running-induced adaptations in 10-14-wk-old C57BL/6J male and female mice subjected to voluntary running or in male mice subjected to forced treadmill running. We evaluated renal perfusion with contrast-enhanced ultrasound and assessed kidney function by measuring the ability to clear a volume load. In addition, we performed flow cytometry, cytokine array, histopathology, and bulk mRNA sequencing. We found that exercise significantly increased cortical microvascular blood volume (P = 0.0085), as indicated by increased plateau contrast signal intensity. In addition, exercised male, but not female, mice excreted significantly more urine in the first hour after a saline bolus (P = 0.0055). At the cellular level, we observed a significant increase in kidney resident macrophages (KRMs; CD45+CD11b+F4/80hi) after treadmill training in male mice. Finally, bulk mRNA sequencing suggested that treadmill training induced changes relating to water and sodium handling as well as angiogenesis and wound healing. These data suggest that exercise alters the immune landscape of the kidney, increases renal microvascular volume, and improves sensitivity of the pressure diuresis response. Future studies will test the hypothesis that macrophages cause the functional adaptations observed.NEW & NOTEWORTHY The kidneys exhibit functional and cellular adaptations to exercise, such as increased renal cortex microvascular volume, as indicated by increased signal intensity of contrast-enhanced ultrasound. Exercise improves efficiency of pressure diuresis in male mice, reducing time needed to excrete an isotonic volume excess. At the cellular level, exercise expands kidney resident macrophage populations and alters transcriptional pathways relating to water and sodium handling, angiogenesis, and wound healing.

Organ health and function depend on communication between cell types to coordinate tissue growth and repair. Recent studies have indicated that fibroblasts are critical to this process; however, their role in regulating inflammatory responses to injury have remained ambiguous. Here, we demonstrate that transforming growth factor β-activated kinase 1 (TAK1) is a gatekeeper of the inflammatory cardiac fibroblast phenotype. We find that TAK1 propagates IL-1β and TNF-α signaling in cardiac fibroblasts and coordinates the synthesis and secretion of chemokines as well as inflammatory and pro-resolving lipid mediators. Deletion of TAK1 in fibroblasts decreased immune cell recruitment after MI, which was associated with improved cardiac structural and functional remodeling in male mice. Nevertheless, we found the effects of TAK1 deletion to be sexually dimorphic in nature, providing support to the idea that the protected phenotype of the female sex may be based in disparate immune and inflammatory responses. Moreover, TAK1 signaling controlled the acquisition of novel markers of the inflammatory fibroblast phenotype, having a biological basis in redox stress, chemokine and lipid mediator biosynthesis, metalloproteinase activity, and damage-associated molecular pattern recognition. Collectively, these results further resolve the nature and function of inflammatory cardiac fibroblasts in cardiac responses to injury and identify TAK1 signaling in fibroblasts as a potential target for therapy.

Background: Many benefits related to exercise are ascribed to reduction in cardiovascular disease risk. Yet, the impact of exercise after the event—i.e., during ventricular remodeling after myocardial infarction (MI)—is unresolved. Because physical exercise alters myocardial structure and function in the healthy heart, it is reasonable to wager that exercise can also impact the remodeling heart. Unfortunately, the mechanism and magnitude of impact of exercise on ventricular remodeling following MI is largely unexplored. Goal: Establish whether and the extent to which exercise impacts ventricular remodeling post-MI. Methods: Twenty-six adult male mice were subjected to non-reperfused MI. Five days after MI, echocardiography was performed, and the next day mice were allocated into Exercise (EXE; n=13) or Sedentary (SED; n=13) groups based on ventricular dysfunction. EXE mice were single housed and given ad libitum access to a voluntary exercise wheel for the duration of the study; SED mice had no wheel access. Mice in the EXE group ran an average of 9 km/d. An exercise capacity test and echocardiography were performed at the end of the five-week protocol and tissue was harvested. Results: Ventricular chambers were significantly larger (p<0.05) in the EXE group than the SED group. These unexpected findings, along with an observed trend towards improved survival in the EXE group led us to ponder the potential implications. Because the study design included a pre-treatment (but post-MI) echocardiogram, we assessed a potential relationship between survival and starting chamber dimensions. Of the mice with the largest chamber dimensions (i.e., >100 µL), 0% of the SED mice survived while 62% of the EXE mice survived. Conclusions: This study affirms the positive impact of exercise following MI. Furthermore, the benefits of exercise may be most noticeable in subjects with the most severe ventricular dilation.

Subverting the host immune response to inhibit inflammation is a key virulence strategy of Yersinia pestis . The inflammatory cascade is tightly controlled via the sequential action of lipid and protein mediators of inflammation. Because delayed inflammation is essential for Y . pestis to cause lethal infection, defining the Y . pestis mechanisms to manipulate the inflammatory cascade is necessary to understand this pathogen’s virulence. While previous studies have established that Y . pestis actively inhibits the expression of host proteins that mediate inflammation, there is currently a gap in our understanding of the inflammatory lipid mediator response during plague. Here we used the murine model to define the kinetics of the synthesis of leukotriene B4 (LTB 4 ), a pro-inflammatory lipid chemoattractant and immune cell activator, within the lungs during pneumonic plague. Furthermore, we demonstrated that exogenous administration of LTB 4 prior to infection limited bacterial proliferation, suggesting that the absence of LTB 4 synthesis during plague contributes to Y . pestis immune evasion. Using primary leukocytes from mice and humans further revealed that Y . pestis actively inhibits the synthesis of LTB 4 . Finally, using Y . pestis mutants in the Ysc type 3 secretion system (T3SS) and Yersinia outer protein (Yop) effectors, we demonstrate that leukocytes recognize the T3SS to initiate the rapid synthesis of LTB 4 . However, several Yop effectors secreted through the T3SS effectively inhibit this host response. Together, these data demonstrate that Y . pestis actively inhibits the synthesis of the inflammatory lipid LTB 4 contributing to the delay in the inflammatory cascade required for rapid recruitment of leukocytes to sites of infection.

Background: Low-dose aspirin is ineffective for primary prevention of cardiovascular events in people with body weight greater than 70kg. While the prevalent explanation for this is reduced platelet cyclooxygenase-1 (COX-1) inhibition at higher body weights, supporting data are limited, thereby demanding further investigation of the reason(s) underlying this observation. We propose that aspirin-mediated cyclooxygenase-2 (COX-2) acetylation and the resulting synthesis of 15-epi-lipoxin A4, a specialized pro-resolving mediator, is suboptimal in higher weight individuals, which may contribute to the clinical trial findings. Methods: To test this hypothesis, we are conducting a double-blind, placebo-controlled, randomized, mechanistic crossover trial. Healthy men and women exhibiting a wide range of body weights take 81mg aspirin and 325mg aspirin for 3 weeks each, following 3-week placebo run-in and wash-out phases. Our target sample size is 90 subjects, with a minimum of 72 completing all visits estimated to be necessary to achieve power adequate to test our primary hypothesis. Our primary endpoint is the difference in change in plasma 15-epi-lipoxin A4 occurring with each dose of aspirin. Secondary endpoints include lipid mediator profiles, serum bioactive lipid profiles, and other endpoints involved in the resolution of vascular inflammation. Conclusions: Study enrollment began in November 2021 and is ongoing. The results of this study will improve our understanding of the mechanisms underlying aspirin’s role(s) in the prevention of adverse cardiovascular outcomes. They may also lead to additional studies with the potential to inform dosing strategies for patients based on body weight. Trial registration: This trial is registered with ClinicalTrials.gov identifier NCT04697719.

Introduction: Resident cardiac fibroblasts are often defined by their extraordinary capacity to deposit extracellular matrix after cardiac injury; however, fibroblasts also react avidly to pro-inflammatory stimuli, suggesting that they may also be mediators of inflammation. Initially identified as a TGFβ responsive enzyme, TGF-β activated kinase 1 (TAK1) has been shown to be significant in regulating pro-inflammatory signaling in several disease models. The goal of this study was to understand how fibroblasts integrate pro-inflammatory signals to regulate acute inflammation following myocardial infarction (MI). We hypothesize that cardiac fibroblasts utilize a TAK1-dependent mechanism to integrate pro-inflammatory signals and orchestrate the cellular immune response following injury. Methods and Results: To create a fibroblast-specific model for TAK1 knockdown, TAK1 fl/fl mice were bred to Col1a2-CreERT mice. Following 2 weeks of tamoxifen chow feeding, both Cre− and Cre+ TAK1 fl/fl mice underwent permanent coronary ligation to induce MI. Three days following MI, immune cell populations from the heart, spleen, and peripheral blood were evaluated through flow cytometry. Deletion of TAK1 in fibroblasts in vivo diminished neutrophils and Ly6C low patrolling monocytes populations in the heart and decreased the number of CCR2neg resident macrophages after MI (n=10/group; p<0.05). Interestingly, circulating levels of neutrophils in the peripheral blood as well as those in the spleen were not significantly different between the groups. To determine how TAK1 may regulate pro-inflammatory signaling, isolated cardiac fibroblasts from TAK1 fl/fl mice were treated with Ad-CMV-iCre and were subsequently treated with IL1β. Notably, TAK1 knockdown suppressed IL1β-dependent p-JNK and NFκB signaling as well as MMP3 production. Further LC-MS/MS evaluation of lipid mediators in conditioned medium showed that deletion of TAK1 significantly increased fibroblast-derived resolvins (RvE2, RvD1, RvD4, RvE4) and lipoxins (LXA4, 15( R)-LXA4) (n= 3-5; p<0.05). Conclusion: Resident cardiac fibroblasts regulate the acute immune response following MI via a TAK1-dependent mechanism. Secreted factors derived from cardiac fibroblasts likely play a pivotal role in shaping the inflammatory and immune response after MI. NIH and AHA. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Diet-induced adipose tissue (AT) inflammation is associated with obesity and the development of systemic insulin resistance. Our lab has shown that specialized proresolving mediators (SPMs), which are induced by exercise (Exe), restore insulin sensitivity and promote resolution of adipose tissue resolution. In this study, we sought to determine if exercise-enhanced production of SPMs extends to adipose tissue and has dietary dependence. Compared with sedentary controls (Sed), mice exposed to 4 wk of Exe display elevated AT expression of SPM biosynthetic enzyme Alox15 (Sed 1.12±0.18 vs. Exe 1.68±0.13 relative expression, n =5-7), SPM levels (Sed vs. Exe; RvD1 156.7±12.02 vs. 223.0±24.71; 17 R -RvD1 354.0±35.86 vs. 534.4±98.92; RvD4 31.31±6.93 vs. 123.1±30.69; and 17 R -RvD3 2.92±1.08 vs. 8.20±1.70 pg/g, n =5-7), and proresolving M2 macrophages (F4/80 + CD301 + ; Sed 17.5±3.2 vs. Exe 40.9±4.5 %F4/80 + , n =4-6). These changes were dependent upon diet as 6-weeks of high fat diet (60% kcal from fat; HFD) feeding abrogated the proresolving effect of exercise when compared with low fat diet fed (10% kcal from fat; LFD) controls—despite performing the same amount of exercise. Interestingly, exercise-induced epinephrine (Epi) production (LFD Sed 147.2±24.4 vs Exe 312.5±60.9 ng/mL) was inhibited by HFD (Sed 121.1±22.7 vs. Exe 140.0±16.8 ng/mL). HFD feeding resulted in diminished expression of the Epi biosynthetic enzyme phenylethanolamine N-methyltransferase (PNMT) in adrenal glands (protein expression: LFD 1.0±0.25 vs. HFD 0.36±0.15, n =4). Moreover, Sed HFD fed animals treated with Epi (0.1 mg/kg i.p. daily) for 1 wk display increased abundance of proresolving adipose tissue macrophages (F4/80 + CD301 + ; Sed 17.8±0.6 vs. Exe 25.2±3.1 %F4/80 + , n =6-7). These results suggest that the resolution promoting effect of exercise in adipose tissue is controlled by high fat diet consumption and adrenergic stimulation.

Results of human and animal studies independently suggest that either ambient fine particulate matter (PM2.5) air pol-lution exposure or a disturbed circadian rhythm (circadian dyssynchrony) are important contributing factors to the rapidly evolving type-2-diabetes (T2D) epidemic. The objective of this study is to investigate whether circadian dyssynchrony increases the susceptibility to PM2.5 and how PM2.5 affects metabolic health in circadian dyssynchrony. We examined systemic and organ-specific changes in glucose homeostasis and insulin sensitivity in mice maintained on a regular (12/12 h light/dark) or disrupted (18/6 h light/dark, light-induced circadian dyssynchrony, LICD) light cycle exposed to air or concentrated PM2.5 (CAP, 6 h/day, 30 days). Exposures during Zeitgeber ZT3-9 or ZT11-17 (Zeitgeber in circadian time, ZT0 = begin of light cycle) tested for time-of-day PM2.5 sensitivity (chronotoxicity). Mice transgenic for lung-specific overexpression of extracellular superoxide dismutase (ecSOD-Tg) were used to assess the contribution of CAP-induced pulmonary oxidative stress. Both, CAP exposure from ZT3-9 or ZT11-17, decreased glucose tolerance and insulin sensitivity in male mice with LICD, but not in female mice or in mice kept on a regular light cycle. Although changes in glucose homeostasis in CAP-exposed male mice with LICD were not associated with obesity, they were accompanied by white adipose tissue (WAT) inflammation, impaired in-sulin signaling in skeletal muscle and liver, and systemic and pulmonary oxidative stress. Preventing CAP-induced ox-idative stress in the lungs mitigated the CAP-induced decrease in glucose tolerance and insulin sensitivity in LICD. Our results demonstrate that circadian dyssynchrony is a novel susceptibility state for PM2.5 and suggest that PM2.5 by in-ducing pulmonary oxidative stress increases glucose intolerance and insulin resistance in circadian dyssynchrony.

Red blood cells (RBCs) are the most abundant cell type in the body and are traditionally appreciated for their role in respiration and gas exchange. Recently, however, RBCs have garnered new attention for their immunomodulatory effects which is primarily achieved via their interaction with resident macrophages in the spleen, known as red pulp macrophages. As RBCs enter the spleen, red pulp macrophages probe the cells for signs of mechanical and oxidative damage, as well as inflammatory stimuli bound to cell surface receptors (e.g., foreign pathogens, endogenous chemokines). Once recognized, red pulp macrophages prune damaged portions of RBC membranes or phagocytose the cell entirely, efficiently processing and recycling the cellular cargo of the RBC. In a healthy human, this process, termed erythrophagocytosis, accounts for the daily turnover of roughly 150-200 billion RBCs. Consequently, defects in the system can have wide-ranging health effects including anemia, impaired host defense, and even sepsis. Recent data suggest that arachidonic acid (AA)-derived prostaglandins promote erythrophagocytosis, yet the impact of other eicosanoid species on the process has not been well described. We performed targeted lipidomics analyses focused on the AA metabolome in two distinct models of erythrophagocytosis. First, mouse bone marrow-derived macrophages were incubated with freshly isolated RBCs; then, spleens from mice were collected following exogenous delivery of damaged RBCs. In both models, we found increased production of the 15( R )-epimer of lipoxin A 4 (15( R )-LXA 4 ), as well as its biosynthetic intermediate, 15-HETE. Similar to LXA 4 , 15( R )-LXA 4 has been shown to robustly promote the active resolution of inflammation by regulating leukocyte function via its interaction with the G protein-coupled receptor, ALX/FPR2. In mice genetically deficient in this receptor, we measured a significant decrease in splenic clearance of damaged RBCs. Together, these data suggest that 15( R )-LXA 4 activation of ALX/FPR2 on red pulp macrophages may be a critical aspect regulating erythrophagocytosis and maintaining RBC homeostasis.

Introduction: The human diet consists of a complex mixture of fatty acids with differential effects on cardiovascular health. Saturated fatty acids have been shown to exert a hypercholesterolemic effect, while omega-3 polyunsaturated fatty acids have anti-inflammatory properties. Advanced statistical approaches are needed however to address whether their covarying relationships may contribute to varying outcomes on cardiovascular health. Methods: We used data on adult participants from the 2003-2004 and 2011-2012 National Health and Nutrition Examination Survey. Blood lipid levels were measured in 2,926 participants, and C-reactive protein (CRP) was measured in 1,339 participants. Fatty acids were measured in serum or plasma and analyzed as the percentage of total fatty acids. We used covariate-adjusted quantile g-computation to assess the joint effects of 6 saturated, 6 monounsaturated, and 11 polyunsaturated fatty acids on log-transformed outcomes, as well as examine the relative contribution of each fatty acid to the joint mixture effect. Results: We estimated positive associations between the mixture of saturated fatty acids with total cholesterol and LDL, which was primarily driven by myristic acid and docosanoic acid. The mixture of monounsaturated fatty acids was associated with lower total cholesterol and LDL, but higher CRP with a quartile increase in monounsaturated fatty acids associated with 21.1% (95% CI: 7.9, 35.9) higher CRP. The mixture of omega-6 polyunsaturated fatty acids was positively associated with both total cholesterol and LDL. We found that the mixture of omega-3 polyunsaturated fatty acids was negatively associated with CRP and LDL. A quartile increase in omega-3 fatty acids was associated with -11.6% (95% CI: -18.8, -3.7) lower CRP, and -2.1% (95% CI: -3.6, -0.4) lower LDL. The relationship with CRP was primarily driven by docosapentaenoic n-3 acid and eicosapentaenoic acid, while the relationship with LDL was driven by docosapentaenoic n-3 acid and docosahexaenoic acid. Conclusions: Assessing the complex mixture of fatty acids, we found distinct beneficial relationships between omega-3 fatty acids with inflammation and lipid profiles, with an important role of docosapentaenoic n-3 acid.

Introduction: The heart is particularly vulnerable to age-related dysfunction, with left ventricular hypertrophy and diastolic dysfunction developing in late life. In this study, we used deep network tracing to elucidate the effects of aging on glucose metabolism in the heart and peripheral tissues of a mouse model of late-life cardiac dysfunction. Hypothesis: Aging processes in the heart are mediated through altered nucleotide metabolism. Methods: Young (12–16 wk, n =6) and aged (80–84 wk, n =6) male C57BL/6J mice were subjected to treadmill exercise capacity tests and echocardiographic measurements. To delineate the effects of age on in vivo glucose metabolism, we delivered 13 C 6 -glucose to mice via a liquid diet and analyzed 13 C enrichment and the relative abundance of metabolites in the heart, liver, and skeletal muscle by ion exchange chromatography-mass spectrometry. Results: Compared with young mice, aged mice had lower exercise capacity (257.3 vs. 394.2 meters distance, p =0.0002 and 0.9 vs. 1.4 kg/m work, p =0.07), which was associated with a 1.3–fold increase in left ventricular mass ( p =0.0006) and longer isovolumetric relaxation time (IVRT: 12.3 vs. 14.1 ms, p =0.03). Although no significant differences in 13 C enrichment were found for metabolites in the glycolysis and tricarboxylic acid cycle pathways, we found 1.2- to 1.5-fold difference in 13 C enrichment ( p <0.05) in purine (AMP, ADP, ATP and GMP, GDP, GTP) and pyrimidine (UMP, UDP, UTP, uridine, orotidine) metabolites. Additionally, aged hearts had 2.4-fold higher levels of the pyrimidine precursor N-carbamoyl L-aspartate. Similar changes were detected in the pyrimidine metabolite pool in aged liver, but not skeletal muscle. Conclusions: These data indicate that altered nucleotide biosynthesis is a prominent metabolic feature of cardiac and liver aging and could provide novel insights into age-related decrements in cardiovascular health.