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

Abstract

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.

PTEN inhibition attenuates endothelial cell apoptosis in coronary heart disease via modulating the AMPK–CREB–Mfn2‐mitophagy signaling pathway

“…When mitophagy is activated, the reactive oxygen species (ROS) produced by the mitochondria are removed, cellular calcium overload is alleviated via reduced mitochondrial calcium leakage, and mitochondria‐mediated apoptosis is inhibited via the limited release of mitochondrial proapoptotic factors (DeLeon‐Pennell et al, ). Through the timely repair of damaged mitochondria, mitophagy maintains mitochondrial quality and quantity and cellular homeostasis (Bagati et al, ).…”

“…When mitophagy is activated, the reactive oxygen species (ROS) produced by the mitochondria are removed, cellular calcium overload is alleviated via reduced mitochondrial calcium leakage, and mitochondria-mediated apoptosis is inhibited via the limited release of mitochondrial proapoptotic factors (DeLeon-Pennell et al, 2018).…”

Resveratrol attenuates cerebral ischaemia reperfusion injury via modulating mitochondrial dynamics homeostasis and activating AMPK‐Mfn1 pathway

“…Mfn1 promotes the fusion between fragmented mitochondria and sustains mitochondrial membrane potential . In addition, Mfn1‐mediated mitochondrial protection also inhibits the mitochondrial apoptosis in several disease models such as atherosclerotic lesions, heart failure, ageing and kidney injury . Interestingly, this concept has not been verified in the model of cerebral IRI.…”

Macrophage functions in wound healing

“…Activin (Bamberger et al, ; Fumagalli et al, ); AREG, Amphiregulin (Chiarini, Freddi, Liu, Armato, & Dal, ; Arg1, Arginase‐1 (Campbell, Saville, Murray, Cruickshank, & Hardman, ; Cash et al, ); ATF3, Activating transcription factor 3 (Landén, Li, & Ståhle, ); CCL, Chemokine (C‐C motif) ligand (Balaji et al, ); CSF1R, Macrophage colony‐stimulating factor 1 receptor (Balaji et al, ); CX3CR1, fractalkine receptor (Balaji et al, ); FGF, Fibroblast growth factor (Eming, Martin, & Tomic‐Canic, ); Gal‐3, Galectin 3 (Dings, Miller, Griffin, & Mayo, ); GR, glucocorticoid receptor (Landen et al, ); IGF, Insulin‐like growth factor 1 (Balaji et al, ); IL, Interleukin (Chiarini et al, ; King, Balaji, Le, Crombleholme, & Keswani, ); IRF, Interferon regulatory factor (Serra et al, ); LXR, Liver X receptor (DeLeon‐Pennell et al, ); NOs, Nitric oxide synthase (Landen et al, ); PDGF, Platelet‐derived growth factor (Eming et al, ); SOCS, Suppressor of cytokine signaling (Feng et al, ); STAT1–3, Signal transducer and activator of transcription 1–3 (Song et al, ; Zhou et al, 2016); TGF, Transforming growth factor (Pakyari, Farrokhi, Maharlooei, & Ghahary, ; Sun et al, ); TNFα, Tumor necrosis factor α (Ashcroft et al, ); VEGFα, Vascular endothelial growth factorα (Eming et al, ; Wilgus, Ferreira, Oberyszyn, Bergdall, & DiPietro, ); Wnt, Wingless type proto‐oncogene (Shi et al, ; Sun et al, ).…”