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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.
Highlights
The average age for a first myocardial infarction (MI) is 65 years for men and 72 years for women [4]
In addition to these 4 genes, Cxcl4 and tissue inhibitor of matrix metalloproteinase (TIMP)-3 were lower in young female mice compared to males
The most salient findings were: (1) in vivo, young female mice were more efficient than young males or old mice of either sex at resolving the inflammatory response through differences in neutrophil physiology; (2) in vitro, neutrophils from males stimulated with apo F activated the liver X receptors/retinoid X receptor (LXR/RXR) pathway through CD36 and PPARγ activation
Summary
The average age for a first myocardial infarction (MI) is 65 years for men and 72 years for women [4]. Following MI, the left ventricle (LV) undergoes a wound healing response that involves necrotic tissue removal and deposition of a replacement scar composed of extracellular matrix proteins. Immune cells polarize to a pro-inflammatory state and release enzymes such as matrix metalloproteinases (MMPs) and reactive oxygen species (ROS) that catalyze necrotic tissue removal [16, 18, 48]. Women have a more temperate response to inflammatory stimuli; for example, in sepsis and atherosclerosis, they have lower pro-inflammatory leukocyte-mediated inflammation and accelerated resolution of inflammation compared to men [66, 71]. Whether and to what extent sex differences exist in the post-MI inflammatory and wound healing response has not been previously examined
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