Genetic deletion of 12/15 lipoxygenase promotes effective resolution of inflammation following myocardial infarction

Sex differences in heart failure development following myocardial infarction (MI) are not fully understood. We hypothesized that differential MI signaling could explain variations in outcomes. Analysis of the mouse heart attack research tool 1.0 (422 mice; young = 5.4 ± 0.1; old = 23.3 ± 0.1 months of age) was used to dissect MI signaling pathways, which was validated in a new cohort of mice (4.8 ± 0.2 months of age); and substantiated in humans. Plasma collected at visit 2 from the MI subset of the Jackson Heart Study (JHS; a community-based study consisting of middle aged and older adults of African ancestry) underwent glycoproteomics grouped by outcome: (1) heart failure hospitalization after visit 2 (n = 3 men/12 women) and (2) without hospitalization through 2012 (n = 24 men/21 women). Compared to young male mice, the infarct region of young females had fewer, but more efficient tissue clearing neutrophils with reduced pro-inflammatory gene expression. Apolipoprotein (Apo) F, which acts upstream of the liver X receptors/retinoid X receptor (LXR/RXR) pathway, was elevated in the day 7 infarcts of old mice compared to young controls and was increased in both men and women with heart failure. In vitro, Apo F stimulated CD36 and peroxisome proliferator-activated receptor (PPAR)γ activation in male neutrophils to turn off NF-κB activation and stimulate LXR/RXR signaling to initiate resolution. Female neutrophils were desensitized to Apo F and instead relied on thrombospondin-1 stimulation of CD36 to upregulate AMP-activated protein kinase, resulting in an overall better wound healing strategy. With age, female mice were desensitized to LXR/RXR signaling, resulting in enhanced interleukin-6 activation, a finding replicated in the JHS community cohort. This is the first report to uncover sex differences in post-MI neutrophil signaling that yielded better outcomes in young females and worse outcomes with age.Electronic supplementary materialThe online version of this article (10.1007/s00395-018-0699-5) contains supplementary material, which is available to authorized users.

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“…Our results highlight the need to not only understand mechanisms that dampen but also mechanisms that turn off inflammation [27, 33, 35, 36]. …”

Section: Discussionmentioning

confidence: 94%

LXR/RXR signaling and neutrophil phenotype following myocardial infarction classify sex differences in remodeling

et al. 2018

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“…Additionally, CAP advanced the preactivation of neutrophils in the spleen pre‐MI and this was confirmed using live and dead cell quantitation. Furthermore, CAP‐mediated splenocardiac leukocyte death was validated using TUNEL staining, which showed inflammation resolution deficiency and impeded biosynthesis of cardio‐protective cypoxins in mice and humans . Interestingly, splenic Mϕ death was mainly in the marginal zone, suggestive of a defective antigen‐presenting process to B and or T cells, which is beyond the scope of current investigation.…”

Section: Discussionmentioning

confidence: 90%

“…G). Arachidonic acid is also a substrate for cytochrome P450 (CYP) epoxygenases to biosynthesize cypoxins (epoxyeicosatrienoic acid (EETs) majorly; 5,6‐, 8,9‐, 11,12‐, and 14,15‐EET) that facilitate survival and resolution of inflammation in mice and human HF . To answer whether cypoxin biosynthesis was impaired by subacute CAP treatment, we measured mRNA levels of Ephx2 , which encodes for soluble epoxide hydrolase, an enzyme that degrades EETs.…”

Section: Resultsmentioning

confidence: 99%

“…The neutrophils (Ly6G + ) in –CAP‐no‐MI, –CAP‐MI‐d1, +CAP‐no‐MI, and +CAP‐MI‐d1 were isolated using magnetic beads, as previously described …”

Section: Methodsmentioning

confidence: 99%

“…As COX generates PGs, likewise, the LOX and CYP pathway respectively biosynthesize novel and orthodox lipid mediators using the common substrate such as essential fatty acids . COX biosynthesizes families of prostanoids (prostaglandins and thromboxanes), LOX generates specialized pro‐resolving mediators and CYP biosynthesizes EETs . After subacute CAP treatment, we determined the inflammation‐resolution nexus within 24 h of cardiac injury to define the role of the splenocardiac axis in cardiac healing.…”

Section: Introductionmentioning

confidence: 99%

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Subacute treatment of carprofen facilitate splenocardiac resolution deficit in cardiac injury

Halade

Kain

Wright

et al. 2018

Journal of Leukocyte Biology

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Inflammation-limiting nonsteroidal pain relievers magnify myocardial infarction (MI) incidences and increase re-admission events in heart failure (HF) patients. However, the molecular and cellular mechanism of this provocative adverse effect is unclear. Our goal was to determine whether carprofen (CAP) impedes splenic leukocyte-directed acute inflammation-resolving response in cardiac injury. After subacute CAP treatment, mice were subjected to permanent coronary ligation maintaining MI- and naïve-controls. Spleen and left ventricle (LV) leukocytes were quantitated using flow cytometry pre- and 24 h post-MI. The inflammation resolution mediators were quantified using mass spectrometry while splenocardiac apoptosis and leukocyte phagocytosis were measured by immunofluorescence and ImageStream, respectively. Subacute CAP treatment promoted strain and cardiac dysfunction before MI and coronary occlusion showed signs of acute HF in CAP and MI-controls. Subacute CAP-injected mice had pre-activated splenic neutrophils, an over activated "don't eat me" signal (CD47) with reduced total Mϕs (F4/80 ) and reparative Mϕs (F4/80/Ly6C /CD206) compared with control in LV and spleen. Post-MI, CAP pre-activated neutrophils (Ly6G ) were intensified and reduced reparative neutrophils (Ly6G /CD206 ) and Mϕs (F4/80/Ly6C ) in LV was indicative of non-resolving inflammation compared with MI-control. Subacute CAP treatment deferred neutrophil phagocytosis functions in the spleen and LV and was more evident post-MI compared with MI-control. CAP pre-activated splenic neutrophils that tailored the Mϕ phagocytosis thereby increased splenocardiac leukocyte death. CAP over amplified COX-1 and COX-2 compared with MI-control and failed to limit prostaglandins and thromboxane in post-MI setting. Further, CAP reduced cardiac-protective epoxyeicosatrienoic acids and over amplified pyrogenic inflammatory cytokines and reduced reparative cytokines, thereby non-resolving inflammation.

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12(S)‐hydroxyeicosatetraenoic acid is significantly increased in diabetic kidney disease and associated with renal function decline

Jin

Sun

et al. 2022

Diabetes Metabolism Res

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Aims: 12(S)-hydroxyeicosatetraenoic (12(S)-HETE), an alternate arachidonic acid metabolite, has been recently examined in metabolic disease. However, the role of 12(S)-HETE in diabetic kidney disease (DKD) remains unclear. We studied for the first time the relationship of serum 12(S)-HETE and DKD and renal function parameters in a Chinese population. Materials and Methods:We recruited 275 subjects who were diagnosed with type 2 diabetes (T2DM) for more than 10 years, including 149 DKD patients and 126 T2DM patients without DKD. Serum 12(S)-HETE was measured using the enzymelinked immunosorbent assay.Results: Serum 12(S)-HETE was significantly higher in DKD patients than controls [384.69 (77.54, 1003.05) pg/ml and 17. 77 (8.11, 75.13) pg/ml, respectively, p < 0.0001]. Compared to controls, 12(S)-HETE was significantly increased in both macroalbuminuria and microalbuminuria groups (p < 0.0001). Further, the macroalbuminuria group also had a higher serum 12(S)-HETE level compared to the microalbuminuria group (p = 0.0063). Moreover, serum 12(S)-HETE was positively correlated with the albuminuria level (r = 0.5833, p < 0.0001), serum creatinine (r = 0.2725, p < 0.0001), and was negatively associated with the estimated glomerular filtration rate (r = −0.2085, p = 0.0005). Further, receiver operating characteristic analysis (ROC) revealed that 12(S)-HETE had a good performance of distinguishing DKD from controls (AUC 0.828) with a sensitivity of 0.913 and a specificity of 0.711. Conclusion:Our findings revealed that serum 12(S)-HETE significantly associated with DKD and disease severity, suggesting that serum 12(S)-HETE may be used as a potential biomarker for the early diagnosis of DKD.

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Genetic deletion of 12/15 lipoxygenase promotes effective resolution of inflammation following myocardial infarction

Cited by 41 publications

References 45 publications

LXR/RXR signaling and neutrophil phenotype following myocardial infarction classify sex differences in remodeling

LXR/RXR signaling and neutrophil phenotype following myocardial infarction classify sex differences in remodeling

Subacute treatment of carprofen facilitate splenocardiac resolution deficit in cardiac injury

12(S)‐hydroxyeicosatetraenoic acid is significantly increased in diabetic kidney disease and associated with renal function decline

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