Structure-Dependent Immune Modulatory Activity of Protegrin-1 Analogs.
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ABSTRACT:
SUBMITTER: Zughaier SM
PROVIDER: S-EPMC4472440 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The known angiotensin II (AngII) physiological effect of aldosterone synthesis and secretion induction, a steroid hormone that contributes to the pathology of postmyocardial infarction (MI) heart failure (HF), is mediated by both Gq/11 proteins and ?-arrestins, both of which couple to the AngII type 1 receptors (AT1Rs) of adrenocortical zona glomerulosa (AZG) cells. Over the past several years, AngII analogs with increased selectivity ("bias") toward ?-arrestin-dependent signaling at the AT1R have been designed and described, starting with SII, the gold-standard ?-arrestin-"biased" AngII analog. In this study, we examined the relative potencies of an extensive series of AngII peptide analogs at relative activation of G proteins versus ?-arrestins by the AT1R. The major structural difference of these peptides from SII was their varied substitutions at position 5, rather than position 4 of native AngII. Three of them were found biased for ?-arrestin activation and extremely potent at stimulating aldosterone secretion in AZG cells in vitro, much more potent than SII in that regard. Finally, the most potent of these three ([Sar(1), Cys(Et)(5), Leu(8)]-AngII, CORET) was further examined in post-MI rats progressing to HF and overexpressing adrenal ?-arrestin1 in vivo. Consistent with the in vitro studies, CORET was found to exacerbate the post-MI hyperaldosteronism, and, consequently, cardiac function of the post-MI animals in vivo. Finally, our data suggest that increasing the size of position 5 of the AngII peptide sequence results in directly proportional increases in AT1R-dependent ?-arrestin activation. These findings provide important insights for AT1R pharmacology and future AngII-targeted drug development.
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Project description:BackgroundThe impact of physical activity on immune response is a hot topic in exercise immunology, but studies involving asthmatic children are scarce. Our aims were to examine whether there were any differences in the level of physical activity and daily TV attendance, to assess its role on asthma control and immune responses to various immune stimulants.MethodsWeekly physical activity and daily television attendance were obtained from questionnaires at inclusion of the PreDicta study. PBMC cultures were stimulated with phytohemagglutinin (PHA), R848, poly I:C, and zymosan. A panel of cytokines was measured and quantified in cell culture supernatants using luminometric multiplex immunofluorescence beads-based assay.ResultsAsthmatic preschoolers showed significantly more TV attendance than their healthy peers (58.6% vs. 41.5% 1-3 h daily and only 25.7% vs. 47.2% ≤1 h daily) and poor asthma control was associated with less frequent physical activity (PA) (75% no or occasional activity in uncontrolled vs. 20% in controlled asthma; 25% ≥3 times weekly vs. 62%). Asthmatics with increased PA exhibited elevated cytokine levels in response to polyclonal stimulants, suggesting a readiness of circulating immune cells for type 1, 2, and 17 cytokine release compared to subjects with low PA and high TV attendance. This may also represent a proinflammatory state in high PA asthmatic children. Low physical activity and high TV attendance were associated with a decrease in proinflammatory cytokines. Proinflammatory cytokines were correlating with each other in in vitro immune responses of asthmatic children, but not healthy controls, this correlation was more pronounced in children with sedentary behavior.ConclusionAsthmatic children show more sedentary behavior than healthy subjects, while poor asthma control is associated with a substantial decrease in physical activity. Our results suggest that asthmatic children may profit from regular exercise, as elevated cytokine levels in stimulated conditions indicate an immune system prepared for responding strongly in case of different types of infections. However, it has to be considered that a hyperinflammatory state in high PA may not be beneficial in asthmatic children.
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