Id3 Is a Novel Atheroprotective Factor Containing a Functionally Significant Single-Nucleotide Polymorphism Associated With Intima–Media Thickness in Humans

Doran, Amanda C.; Lehtinen, Allison B.; Meller, Nahum; Lipinski, Michael J.; Slayton, R. Parker; Oldham, Stephanie; Skaflen, Marcus D.; Yeboah, Joseph; Rich, Stephen S.; Bowden, Donald W.; McNamara, Coleen A.

doi:10.1161/circresaha.109.210294

Cited by 42 publications

(70 citation statements)

References 47 publications

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“…Much of the published research on Id genes is focused on cancer biology, although, in recent years, their function in cardiovascular diseases has attracted attention. Studies have suggested an important role of Id proteins in maintaining vessel homeostasis, and Id proteins have been implicated in angiogenesis and atherosclerosis (4,18,23). Our findings provide a further understanding of the role of Id proteins in the vasculature, particularly in the pathophysiology of PAH.…”

Section: Discussionsupporting

confidence: 54%

Id proteins are critical downstream effectors of BMP signaling in human pulmonary arterial smooth muscle cells

Yang

Li²,

Liu

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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bone morphogenetic protein type II receptor; cell cycle; Id; pulmonary arterial smooth muscle cell; pulmonary hypertension PULMONARY ARTERIAL HYPERTENSION (PAH) is a severe clinical condition associated with a poor prognosis and high mortality. Occlusive remodeling of the distal pulmonary vasculature is the major pathological finding in PAH. Proliferation of myofibroblasts and smooth muscle cells in the pulmonary arterial wall increases pulmonary vascular resistance and elevates pulmonary arterial pressure, ultimately leading to right ventricular failure and eventually death (20,26,29). A greater understanding of the molecular mechanisms involved in pulmonary vascular remodeling will facilitate new approaches for therapy.Bone morphogenetic protein type II receptor (BMPR-II) mutations are responsible for the majority (Ͼ70%)of cases of heritable PAH and have been reported in 15-40% of apparently sporadic idiopathic cases (6, 15, 34). Loss of BMPR-II or dysfunction of BMP signaling are now recognized in several preclinical models of PAH, including those induced by hypoxia, monocrotaline, and high flow (10, 16). BMPs are pleiotropic cytokines involved in a wide range of vascular cell function including proliferation, migration, differentiation, and apoptosis, but how BMPR-II mutations cause these abnormalities remains uncertain.The inhibitor of DNA binding family of proteins (Id proteins) are major downstream mediators of BMP signaling (19). Id proteins are basic helix-loop-helix transcription factors that lack a DNA binding domain. These proteins bind to the ubiquitously expressed E protein family members with high affinity and inhibit their binding to target DNA (5, 11). This special function of Id proteins confers a central role in the regulation of gene expression and hence cell differentiation and proliferation (24,31). Until now, four members of the Id family, Id1-4, have been identified in mammalian cells. They are encoded by separate genes and demonstrate individual expression patterns and protein structure, which may contribute to their different functions. For example, Id2 is largely expressed in immune cells (8,40), and only Id1 lacks the consensus CDK2 phosphorylation site at its NH 2 terminus (5). Our recent study revealed that Id1 and Id2 are induced by BMPs in pulmonary artery smooth muscle cells (PASMCs) through a canonical Smad-dependent pathway (37) and that BMPR-II mutation reduced the BMP-stimulated induction of Id1 and Id2 in these cells. We further showed that Id1 and Id2 are involved in the inhibition of PASMC proliferation by BMP4. We have also shown that agents enhancing BMP/ Smad/Id signaling in PASMCs can restore the growth-suppressive effects of BMPs in BMPR-II mutant cells (38,39).In the present study, we undertook a systematic analysis of the regulation of Id1-4 in PASMCs via a range of growth factors, cytokines, and BMPs. Having identified Id1 and Id3 as major targets of BMP signaling in these cells, we show that the induction of both Id1 and Id3 is dependent on intact BMPR-II and that...

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Section: Discussionsupporting

confidence: 54%

Id proteins are critical downstream effectors of BMP signaling in human pulmonary arterial smooth muscle cells

Yang

Li²,

Liu

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…ID2 was also found to be able to promote endothelial cell growth and migration (3,11). Most recently, ID3 has been shown to be an important atheroprotective factor, and loss of ID3 was linked to increased intima-media thickness (17). Thus ID1, ID2, and ID3 may be important mediators of any pathobiological effects that might accompany endothelial adaptation to altered shear stress.…”

Section: Discussionmentioning

confidence: 96%

Adaptive response of vascular endothelial cells to an acute increase in shear stress magnitude

Zhang

Friedman

2012

American Journal of Physiology-Heart and Circulatory Physiology

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Zhang J, Friedman MH. Adaptive response of vascular endothelial cells to an acute increase in shear stress magnitude. Am J Physiol Heart Circ Physiol 302: H983-H991, 2012. First published December 2, 2011; doi:10.1152/ajpheart.00168.2011.-The adaptation of vascular endothelial cells to shear stress alteration induced by global hemodynamic changes, such as those accompanying exercise or digestion, is an essential component of normal endothelial physiology in vivo. An understanding of the transient regulation of endothelial phenotype during adaptation to changes in mural shear will advance our understanding of endothelial biology and may yield new insights into the mechanism of atherogenesis. In this study, we characterized the adaptive response of arterial endothelial cells to an acute increase in shear stress magnitude in well-defined in vitro settings. Porcine endothelial cells were preconditioned by a basal level shear stress of 15 Ϯ 15 dyn/cm 2 at 1 Hz for 24 h, after which an acute increase in shear stress to 30 Ϯ 15 dyn/cm 2 was applied. Endothelial permeability nearly doubled after 40-min exposure to the elevated shear stress and then decreased gradually. Transcriptomics studies using microarray techniques identified 86 genes that were sensitive to the elevated shear. The acute increase in shear stress promoted the expression of a group of anti-inflammatory and antioxidative genes. The adaptive response of the global gene expression profile is triphasic, consisting of an induction period, an early adaptive response (ca. 45 min) and a late remodeling response. Our results suggest that endothelial cells exhibit a specific phenotype during the adaptive response to changes in shear stress; this phenotype is different than that of fully adapted endothelial cells. permeability; gene expression; microarray ATHEROSCLEROSIS ARISES FROM endothelial cell dysfunction. Endothelial dysfunction features increased permeability, enhanced expression of adhesion molecules and leukocyte adhesion, enhanced cell turnover, increased oxidant stress, and reduced endothelium-dependent vasodilation (51). Increased endothelial permeability leads to the accumulation of LDL in the intima, which is a key step in atherosclerotic development. The inflammatory response of endothelial cells results in the recruitment of monocytes, which migrate into the intima and differentiate into macrophages, which engulf oxidized LDL and form foam cells. The accumulation of foam cells in the intima leads to the formation of atherosclerotic plaques. Therefore, endothelial permeability and inflammatory status greatly affect arterial atherosusceptibility.Endothelial cells in the vasculature are constantly exposed to shear stress. Shear-dependent permeability to macromolecules has been examined both in vitro and in vivo. The application of shear stress to static cultured cells increased endothelial permeability to albumin (32) and dextran (50). However, these increases may have been caused by the transient response of endothelial cells to the onset of shear...

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“…ID3-DEFICIENT MICE 771 Furthermore, in the cauda epididymidis many of the probe sets that were altered by ID3 deficiency are implicated in physiological development (proliferation, differentiation, and apoptosis), whereas the predominantly affected group in the initial segment/caput regions, based on biological function, is the response to stress transcripts. Interestingly, microarray results of primary aortic vascular smooth muscle cells showed that the expression of many genes involved in immune trafficking and apoptosis, as well as cellular movement, proliferation, and adhesion, were modulated significantly in Id3 À/À mice as compared with wild-type controls [36]. Although few studies have examined the impact of Id3 deletion on global gene expression in a particular tissue as we have done here, many have ascertained the transcriptional profiles of specific target genes or described a range of phenotypic outcomes in the absence of Id3.…”

Section: Discussionmentioning

confidence: 99%

Null Mutation of the Transcription Factor Inhibitor of DNA Binding 3 (Id3) Affects Spermatozoal Motility Parameters and Epididymal Gene Expression in Mice

Carroll

Luu

Robaire

2010

Biology of Reproduction

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ID3 is a transcription factor that acts as a dominant-negative regulator of other transcription factors by sequestering them, thus rendering them unable to bind DNA. We have shown previously that ID3 is expressed in a unique, region-specific manner along the epididymis, a highly specialized tissue of the male reproductive tract that functions in the transport and maturation of spermatozoa. The goal of these studies was to test the hypothesis that ID3 plays a role in the epididymis in the region-specific regulation of gene expression that is responsible for establishing the microenvironment required to carry out sperm-related functions. The consequences of ID3 deficiency on epididymal histology and gene expression profiles, as well as spermatozoal motility parameters, were determined. Although ID3 deficiency (Id3(-/-) mice) had no noticeable impact on epididymal histology, the targeted mutation adversely affected sperm motility parameters. Moreover, principal component analysis of microarray data indicated that the gene expression signatures for tissues obtained from Id3(-/-) mice and their genotypic controls were distinct from each other in each epididymal region. The predominant effect of the Id3 null mutation was in the cauda region where the expression of many transcription factors, including Hoxb8 and Bclaf1, was markedly affected. ID3 may play an important role in the molecular circuitry involved in the establishment and maintenance of the region-specific differences in gene expression that are characteristic of the epididymis.

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Id3 Is a Novel Atheroprotective Factor Containing a Functionally Significant Single-Nucleotide Polymorphism Associated With Intima–Media Thickness in Humans

Cited by 42 publications

References 47 publications

Id proteins are critical downstream effectors of BMP signaling in human pulmonary arterial smooth muscle cells

Id proteins are critical downstream effectors of BMP signaling in human pulmonary arterial smooth muscle cells

Adaptive response of vascular endothelial cells to an acute increase in shear stress magnitude

Null Mutation of the Transcription Factor Inhibitor of DNA Binding 3 (Id3) Affects Spermatozoal Motility Parameters and Epididymal Gene Expression in Mice

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