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

• Published in: Basic research in cardiology Vol. 113; no. 5; pp. 40 - 19
• Main Authors: DeLeon-Pennell, Kristine Y., Mouton, Alan J., Ero, Osasere K., Ma, Yonggang, Padmanabhan Iyer, Rugmani, Flynn, Elizabeth R., Espinoza, Ingrid, Musani, Solomon K., Vasan, Ramachandran S., Hall, Michael E., Fox, Ervin R., Lindsey, Merry L.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-09-2018; Springer Nature B.V
• Subjects: Adult; Adults; African Americans; Age; Age Factors; Aged; Aged, 80 and over; AMP; AMP-activated protein kinase; Animals; Apolipoproteins; Cardiology; CD36 antigen; Cell activation; Communities; Databases, Factual; Desensitization; Disease Models, Animal; Female; Females; Gender aspects; Gender differences; Gene expression; Heart attacks; Heart diseases; Heart failure; Heart Failure - ethnology; Heart Failure - metabolism; Heart Failure - pathology; Heart Failure - physiopathology; Humans; Inflammation; Interleukin 6; Interleukins; Kinases; Leukocytes (neutrophilic); Liver; Liver X receptors; Liver X Receptors - metabolism; Male; Medicine; Medicine & Public Health; Men; Mice; Mice, Inbred C57BL; Middle Aged; Myocardial infarction; Myocardial Infarction - ethnology; Myocardial Infarction - metabolism; Myocardial Infarction - pathology; Myocardial Infarction - physiopathology; Myocardium - metabolism; Myocardium - pathology; Neutrophils; Neutrophils - metabolism; NF-κB protein; Older people; Original Contribution; Peroxisome proliferator-activated receptors; Phenotype; Phenotypes; Prognosis; Proteins; Receptors; Retinoid X receptors; Retinoid X Receptors - metabolism; Sex; Sex differences; Sex Factors; Signal Transduction; Signaling; Thrombospondin; United States - epidemiology; Ventricular Function, Left; Ventricular Remodeling; Women; Wound healing; Young Adult; United States; Humans; Neutrophils; Proteomics; Sex differences; Mice; Big data; LXR/RXR
• ISSN: 0300-8428; 1435-1803
• DOI: 10.1007/s00395-018-0699-5

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.