Summary Cells benefit from silencing foreign genetic elements but must simultaneously avoid inactivating endogenous genes. Although chromatin modifications and RNAs contribute to maintenance of silenced states, the establishment of silenced regions will inevitably reflect underlying DNA sequence and/or structure. Here we demonstrate that a pervasive non-coding DNA feature in Caenorhabditis elegans, characterized by 10-basepair periodic An/Tn-clusters (PATCs), can license transgenes for germline expression within repressive chromatin domains. Transgenes containing natural or synthetic PATCs are resistant to position effect variegation and stochastic silencing in the germline. Among endogenous genes, intron length and PATC-character undergo dramatic changes as orthologs move from active to repressive chromatin over evolutionary time, indicating a dynamic character to the An/Tn periodicity. We propose that PATCs form the basis of a cellular immune system, identifying certain endogenous genes in heterochromatic contexts as privileged while foreign DNA can be suppressed with no requirement for a cellular memory of prior exposure.
Dietary consumption of ω-3 polyunsaturated fatty acids (PUFAs), present in fish oils, is known to improve the vascular response, but their molecular targets remain largely unknown. Activation of the TRPV4 channel has been implicated in endothelium-dependent vasorelaxation. Here, we studied the contribution of ω-3 PUFAs to TRPV4 function by precisely manipulating the fatty acid content in Caenorhabditis elegans. By genetically depriving the worms of PUFAs, we determined that the metabolism of ω-3 fatty acids is required for TRPV4 activity. Functional, lipid metabolome, and biophysical analyses demonstrated that ω-3 PUFAs enhance TRPV4 function in human endothelial cells and support the hypothesis that lipid metabolism and membrane remodeling regulate cell reactivity. We propose a model whereby the eicosanoid's epoxide group location increases membrane fluidity and influences the endothelial cell response by increasing TRPV4 channel activity. ω-3 PUFA-like molecules might be viable antihypertensive agents for targeting TRPV4 to reduce systemic blood pressure.
Objectives— The apolipoprotein (apo)A-I mimetic peptide 5A is highly specific for ATP-binding cassette transporter (ABC)A1-mediated cholesterol efflux. We investigated whether the 5A peptide shares other beneficial features of apoA-I, such as protection against inflammation and oxidation. Methods— New Zealand white rabbits received an infusion of apoA-I, reconstituted high-density lipoprotein (HDL) containing apoA-I ([A-I]rHDL), or the 5A peptide complexed with phospholipids (1-palmitoyl-2-linoleoyl phosphatidylcholine [PLPC]), before inserting a collar around the carotid artery. Human coronary artery endothelial cells (HCAECs) were incubated with (A-I)rHDL or 5A/PLPC before stimulation with tumor necrosis factor α. Results— ApoA-I, (A-I)rHDL, and 5A/PLPC reduced the collar-mediated increase in (1) endothelial expression of cell adhesion molecules vascular cell adhesion molecule-1 and intercellular adhesion molecule-1; (2) production, as well as the expression of the Nox4 catalytic subunits of the NADPH oxidase; and (3) infiltration of circulating neutrophils into the carotid intima–media. In HCAECs, both 5A/PLPC and (A-I)rHDL inhibited tumor necrosis factor-α–induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression, as well as the nuclear factor κB signaling cascade and production. The effects of the 5A/PLPC complex were no longer apparent in HCAECs knocked down for ABCA1. Conclusion— Like apoA-I, the 5A peptide inhibits acute inflammation and oxidative stress in rabbit carotids and HCAECs. In vitro, the 5A peptide exerts these beneficial effects through interaction with ABCA1.
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