Involvement of Interleukin-1 Receptor–Associated Kinase-1 in Vascular Smooth Muscle Cell Proliferation and Neointimal Formation After Rat Carotid Injury

Abstract

To investigate the consequences of hybridization between species, we studied three replicate hybrid populations that formed naturally between two swordtail fish species, estimating their fine-scale genetic map and inferring ancestry along the genomes of 690 individuals. In all three populations, ancestry from the "minor" parental species is more common in regions of high recombination and where there is linkage to fewer putative targets of selection. The same patterns are apparent in a reanalysis of human and archaic admixture. These results support models in which ancestry from the minor parental species is more likely to persist when rapidly uncoupled from alleles that are deleterious in hybrids. Our analyses further indicate that selection on swordtail hybrids stems predominantly from deleterious combinations of epistatically interacting alleles. U nderstanding speciation is central to understanding evolution, but so much about the process still puzzles us. Foundational work in evolutionary biology envisioned speciation as an ordered process in which reproductive barriers, once established, prevent gene flow between species (1). We now realize, however, that speciation is much more dynamic, with evidence of historical and ongoing hybridization visible in the genomes of myriad species (2-5). The ubiquity of hybridization raises the question of how species that interbreed remain distinct.At least part of the answer lies in widespread selection on hybrid genomes (1). Analyses of hominin and swordtail fish hybrids indicate that ancestry from the "minor" parent species (the parent that contributed less to the gene pool of hybrids) is decreased near functionally important elements (4, 6, 7), presumably because such regions are enriched for harmful alleles. Aside from these observations, however, little is known about how hybrid genomes evolve. Decades of experimental work have demonstrated that Bateson-Dobzhansky-Muller incompatibilities (BDMIs) are a central mechanism underlying reproductive isolation once species are formed (8-10), but the importance of BDMIs in the evolution of hybrid genomes remains unknown, as does the role of other modes of selection. When there is introgression from a species with a smaller effective population size, hybrids may suffer from increased genetic load ("hybridization load") due to the introduction of weakly deleterious alleles (6,11,12). Depending on the environment in which hybrids find themselves, alleles that underlie ecological adaptations in the parental species may also be deleterious (13,14). Complicating matters further, the sources of selection on hybrids will likely vary from system to system, depending on the extent of genetic and ecological differentiation between the parental species as well as the differences in their effective population sizes.Regardless of the source of selection, however, one feature is expected to play a central role in mediating its effects: variation in recombination rates along the genome (6,11,(15)(16)(17). In models of BDMIs, neutral ancest...

IRAK regulates macrophage foam cell formation by modulating genes involved in cholesterol uptake and efflux

“…An earlier study in mice showed that IRAK1 deletion attenuates atherosclerosis progression [20]. Recent work from our laboratory also demonstrated the role of IRAK1 in rats VSMCs proliferation, an important event in atherosclerosis progression [38]. At the same time enhanced expression of IRAK1 is observed in human atherosclerotic arteries [18].…”

LPS Promotes Vascular Smooth Muscle Cells Proliferation Through the TLR4/Rac1/Akt Signalling Pathway

“…Moreover, blocking the progress of atherosclerosis by inhibiting TLR4-mediated signalling has been verified in different animal models [22-25]. LPS has been shown to activate TLR4 and induce various signalling cascades, including PI3K/Akt [13], mitogen-activated protein kinase [26, 27] and interleukin-1 receptor associated kinase (IRAK) [28, 29]; each of which participates in cell proliferation [30]. However, the underlying molecular mechanisms controlling VSMCs proliferation after LPS stimulation remain to be identified.…”

Down-Regulation of Protein Kinase C-ε by Prolonged Incubation with PMA Inhibits the Proliferation of Vascular Smooth Muscle Cells

“…5C and D). However, others have shown that the silencing of PKC-ε inhibited PDGF-induced ERK 1/2 phosphorylation, indicating that PKC-ε is up-stream of ERK [32]. Regardless of the hierarchy or parallel role of PKC-ε in regulating cell proliferation in relation to ERK, the data presented in Fig.…”

“…A recent study by Jain et al [32] showed an increase in the proliferation of rat VSMCs in an endogenous interleulin-1 receptor-associated kinase-1 (IRAK)-ERK-PKC-ε-dependent manner in a rat balloon injury model. The present data indicate that the phosphorylation of ERK in VSMCs was increased by PMA in a rapid and transient manner.…”