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         headline:LXR/RXR signaling and neutrophil phenotype following myocardial infarction classify sex differences in remodeling
         description: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.
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      headline:LXR/RXR signaling and neutrophil phenotype following myocardial infarction classify sex differences in remodeling
      description: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.
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         Mice
         Humans
         Sex differences
         Neutrophils
         LXR/RXR
         Proteomics
         Big data
         Cardiology
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            name:University of Mississippi Medical Center
            address:
               name:Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, USA
               type:PostalAddress
            type:Organization
      name:Rugmani Padmanabhan Iyer
      affiliation:
            name:University of Mississippi Medical Center
            address:
               name:Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, USA
               type:PostalAddress
            type:Organization
      name:Elizabeth R. Flynn
      affiliation:
            name:University of Mississippi Medical Center
            address:
               name:Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, USA
               type:PostalAddress
            type:Organization
      name:Ingrid Espinoza
      affiliation:
            name:UMMC
            address:
               name:Department of Preventive Medicine and Cancer Institute, UMMC, Jackson, USA
               type:PostalAddress
            type:Organization
      name:Solomon K. Musani
      affiliation:
            name:UMMC
            address:
               name:Jackson Heart Study, UMMC, Jackson, USA
               type:PostalAddress
            type:Organization
      name:Ramachandran S. Vasan
      affiliation:
            name:Boston University School of Medicine
            address:
               name:Section of Preventive Medicine and Epidemiology and Cardiology, Department of Medicine, Boston University School of Medicine, Boston, USA
               type:PostalAddress
            type:Organization
      name:Michael E. Hall
      affiliation:
            name:University of Mississippi Medical Center
            address:
               name:Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, USA
               type:PostalAddress
            type:Organization
            name:UMMC
            address:
               name:Jackson Heart Study, UMMC, Jackson, USA
               type:PostalAddress
            type:Organization
            name:UMMC
            address:
               name:Division of Cardiology, UMMC, Jackson, USA
               type:PostalAddress
            type:Organization
      name:Ervin R. Fox
      affiliation:
            name:UMMC
            address:
               name:Jackson Heart Study, UMMC, Jackson, USA
               type:PostalAddress
            type:Organization
            name:UMMC
            address:
               name:Division of Cardiology, UMMC, Jackson, USA
               type:PostalAddress
            type:Organization
      name:Merry L. Lindsey
      url:http://orcid.org/0000-0002-4090-0391
      affiliation:
            name:University of Mississippi Medical Center
            address:
               name:Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, USA
               type:PostalAddress
            type:Organization
            name:G.V. (Sonny) Montgomery Veterans Affairs Medical Center
            address:
               name:Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, USA
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, USA
      name:Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, USA
      name:Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, USA
      name:Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, USA
      name:Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, USA
      name:Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, USA
      name:Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, USA
      name:Department of Preventive Medicine and Cancer Institute, UMMC, Jackson, USA
      name:Jackson Heart Study, UMMC, Jackson, USA
      name:Section of Preventive Medicine and Epidemiology and Cardiology, Department of Medicine, Boston University School of Medicine, Boston, USA
      name:Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, USA
      name:Jackson Heart Study, UMMC, Jackson, USA
      name:Division of Cardiology, UMMC, Jackson, USA
      name:Jackson Heart Study, UMMC, Jackson, USA
      name:Division of Cardiology, UMMC, Jackson, USA
      name:Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, USA
      name:Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, USA

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