Classical ex vivo experiments suggest that the relaxation of cardiac muscle depends on afterload, with lower afterloads producing faster relaxation (Brutseart et al Circ Res 1980 47(5):637). These original experiments used protocols in which the muscle returned to its original length before beginning diastolic relaxation (black lines, Figure 1). In this experimental mode, reducing afterload increases the velocity of the muscle when as returns to its original length (the end systolic strain rate). In this work, we used electrically simulated rat trabeculae to test the hypothesis that the strain rate, and not the afterload, controls relaxation. We varied the end-systolic strain rate by allowing the trabeculae to relengthen by different amounts at a fixed afterload. Relaxation was slowest when relengthening was minimal (gray lines, Figure 1) and fastest when relengthening was complete (black lines, Figure 1). Preload did not influence this effect. In summary, our preliminary data suggest that is the strain rate at the end of systole, and not the force that the myocardium develops as it contracts, that controls relaxation.
Calcitonin gene-related peptide (CGRP) induces expression of IL-23p19 in endothelial cells (ECs) RD Granstein, W Ding and J Lam Weill Cornell Medicine, New York, NY We have previously shown that the neuropeptide CGRP influences the inflammatory and immune functions of primary dermal microvascular ECs (pDMECs). To expand this line of inquiry, we examined the ability of CGRP to influence EC expression of IL-23p19. IL-23 is a heterodimeric cytokine, composed of p19 and p40 subunits. The murine BALB/c EC line bEND.3 was employed as a surrogate for pDMECs. bEnd.3 cells were plated in 12-well flat bottom plates at 2.5 x 10 5 cells/well and incubated overnight. Culture media was replaced with fresh media the following day and cells cultured in 0 nM, 0.1nM, 1.0nM, 10nM or 100nM of CGRP. A positive control group was treated with 2 mg/mL of LPS. Cells were collected at various timepoints to quantify mRNA levels using real-time PCR. A significant increase in expression of IL-23p19 mRNA was seen at 8 hours. IL-23p40 subunit mRNA was undetectable; this is in accordance with findings by others that ECs do not express IL-23p40. Supernatant IL-23p19 was not detected by ELISA, also in accordance with findings by others. Western blot of cell contents demonstrated greater quantities of intracellular IL-23p19 at both 12 and 24 hours in the CGRP-and LPS-treated groups when compared with untreated cells. The function of intracellular IL-23p19 is not well understood, but it is a member of the IL-6 cytokine family and has been shown to function similarly to IL-6 in some aspects; both bind gp130 and activate STAT3. IL-23p19 expression in ECs has been associated with enhanced cell surface expression of ICAM-1 and VCAM-1, which could augment leukocytes attachment and transendothelial migration. However, in preliminary experiments, exposure of bEND.3 cells to CGRP reduced, rather than enhanced, VCAM-1 and ICAM-1 expression, perhaps because of diverse signaling pathways induced by CGRP. If dermal ECs also respond to CGRP by increasing IL-23p19 expression, neuronal release of CGRP at dermal blood vessels may provide a previously unidentified biologically important signal to dermal ECs.
Achalasia is a rare motility disorder of the esophagus caused by the gradual degeneration of myenteric neurons. Immune-mediated ganglionitis has been proposed to underlie the loss of myenteric neurons. Here, we measure the immune cell transcriptional profile of paired lower esophageal sphincter (LES) tissue and blood samples in achalasia and controls using single-cell RNA sequencing (scRNA-seq). In achalasia, we identify a pattern of expanded immune cells and a specific transcriptional phenotype, especially in LES tissue. We show C1QC+ macrophages and tissue-resident memory T cells (TRM), especially ZNF683+ CD8+ TRM and XCL1+ CD4+ TRM, are significantly expanded and localized surrounding the myenteric plexus in the LES tissue of achalasia. C1QC+ macrophages are transcriptionally similar to microglia of the central nervous system and have a neurodegenerative dysfunctional phenotype in achalasia. TRM also expresses transcripts of dysregulated immune responses in achalasia. Moreover, inflammation increases with disease progression since immune cells are more activated in type I compared with type II achalasia. Thus, we profile the immune cell transcriptional landscape and identify C1QC+ macrophages and TRM as disease-associated immune cell subsets in achalasia.
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