scholarly journals The apelin/APJ system in the regulation of vascular tone: friend or foe?

2020 ◽  
Author(s):  
Yoshiyuki Rikitake
Keyword(s):  
Smooth Muscle ◽  
Vascular Tone ◽  
Molecular Mechanisms ◽  
Pathological Condition ◽  
Critical Role ◽  
Cell Types ◽  
Peptide Ligands ◽  
Type I ◽  
Gene Encoding ◽  
Regulation Of Vascular Tone

Abstract The apelin (APJ) receptor was originally cloned as a gene encoding a putative G protein-coupled receptor related to angiotensin receptor type I. To date, two endogenous peptide ligands for APJ have been identified: apelin and elabela/Toddler. The apelin/APJ system regulates blood pressure and vascular tone. The endothelial and smooth muscle apelin/APJ systems exert opposite actions in the regulation of vascular tone. Binding of apelin to endothelial APJ promotes the release of vasodilators, such as nitric oxide and prostacyclin, leading to vasodilation. Alternatively, binding of apelin to smooth muscle APJ induces vasoconstriction, although the molecular mechanisms of the apelin-induced vasoconstriction are poorly understood. Recently, a critical role for interaction of APJ with α1-adrenergic receptor in the apelin-induced vasoconstriction was reported. The action of apelin on vascular tone may depend upon blood vessel type or pathological condition. Although the apelin/APJ system could serve as a potential therapeutic target for hypertension and cardiovascular disease, the role of this system in various cell types appears to be complicated.

Stable transfer and restricted expression of a cloned class I gene encoding a secreted transplantation-like antigen

1985 ◽  
Vol 5 (6) ◽  
pp. 1295-1300
Author(s):  
Y Barra ◽  
K Tanaka ◽  
K J Isselbacher ◽  
G Khoury ◽  
G Jay
Keyword(s):  
Molecular Mechanisms ◽  
Cell Types ◽  
Class I ◽  
Regulatory Sequences ◽  
Transcriptional Enhancer ◽  
Gene Encoding ◽  
Specific Expression ◽  
Tissue Specific ◽  
Functional Studies ◽  
I Gene

The identification of a unique major histocompatibility complex class I gene, designated Q10, which encodes a secreted rather than a cell surface antigen has led to questions regarding its potential role in regulating immunological functions. Since the Q10 gene is specifically activated only in the liver, we sought to define the molecular mechanisms which control its expression in a tissue-specific fashion. Results obtained by transfection of the cloned Q10 gene, either in the absence or presence of a heterologous transcriptional enhancer, into a variety of cell types of different tissue derivations are consistent with the Q10 gene being regulated at two levels. The first is by a cis-dependent mechanism which appears to involve site-specific DNA methylation. The second is by a trans-acting mechanism which would include the possibility of an enhancer binding factor. The ability to efficiently express the Q10 gene in certain transfected cell lines offers an opportunity to obtain this secreted class I antigen in quantities sufficient for functional studies; this should also make it possible to define regulatory sequences which may be responsible for the tissue-specific expression of Q10.

The developmentally regulated ECM glycoprotein ISG plays an essential role in organizing the ECM and orienting the cells of Volvox

2000 ◽  
Vol 113 (24) ◽  
pp. 4605-4617
Author(s):  
A. Hallmann ◽  
D.L. Kirk
Keyword(s):  
Critical Role ◽  
Somatic Cells ◽  
Cell Types ◽  
Model System ◽  
Swimming Behavior ◽  
Truncated Form ◽  
Developmentally Regulated ◽  
Gene Encoding ◽  
Ecm Architecture ◽  
Multicellular Organisms

Volvox is one of the simplest multicellular organisms with only two cell types, yet it has a surprisingly complex extracellular matrix (ECM) containing many region-specific morphological components, making Volvox suitable as a model system for ECM investigations. ECM deposition begins shortly after inversion, which is the process by which the embryo turns itself right-side-out at the end of embryogenesis. It was previously shown that the gene encoding an ECM glycoprotein called ISG is transcribed very transiently during inversion. Here we show that the developmentally controlled ISG accumulates at the bases of the flagella right after inversion, before any morphologically recognizable ECM structures have yet developed. Later, ISG is abundant in the ‘flagellar hillocks’ that encircle the basal ends of all flagella, and in the adjacent ‘boundary zone’ that delimits the spheroid. Transgenic Volvox were generated which express a truncated form of ISG. These transgenics exhibit a severely disorganized ECM within which the cells are embedded in a highly chaotic manner that precludes motility. A synthetic version of the C-terminal decapeptide of ISG has a similar disorganizing effect, but only when it is applied during or shortly after inversion. We postulate that ISG plays a critical role in morphogenesis and acts as a key organizer of ECM architecture; at the very beginning of ECM formation ISG establishes an essential initial framework that both holds the somatic cells in an adaptive orientation and acts as the scaffold upon which the rest of the ECM can be properly assembled, assuring that somatic cells of post-inversion spheroids are held in orientations and locations that makes adaptive swimming behavior possible.

Abstract MP175: Disruption of the Genome Architecture at the PRRX1 Locus is Associated With the Pathogenesis of LMNA -related Dilated Cardiomyopathy

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Yuan Zhang ◽  
Mohamed Ameen ◽  
Isaac Perea Gil ◽  
Jennifer Arthur ◽  
Alexandra A Gavidia ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Single Cell ◽  
Genome Organization ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Lamin A ◽  
Candidate Locus ◽  
Gene Encoding ◽  
Gene Dysregulation

Background: LMNA , a gene encoding A-type lamin proteins (abbreviated as lamin A), is one of the most frequently mutated genes in dilated cardiomyopathy (DCM). The molecular mechanisms underlying cardiomyocyte dysfunction in LMNA -related DCM remain elusive, translating to the lack of disease-specific therapies. Lamin A has been shown to play a critical role in genome organization via interactions with the chromatin at specific regions called lamina-associated domains (LADs). However, little is known about whether DCM-causing LMNA mutations rearrange the genome conformation and chromosome accessibility. The overarching goal of this study is to define the role of genome organization in LMNA -related DCM. Methods: LMNA -related DCM was modeled in vitro using cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs) from DCM patients carrying a frameshift mutation in the LMNA gene (c. 348_349insG; p. K117fs) and isogenic controls. We combined genome-wide single cell functional genomic and epigenomic mapping analyses to define the gene regulation and cis-regulatory interactions in isogenic iPSC-CMs. Results: Single-cell RNA-seq revealed global gene dysregulation in LMNA mutant compared to isogenic control iPSC-CMs. The homeodomain transcription factor PRRX1 was significantly upregulated in mutant cells. We showed that LAD integrity is disrupted at the PRRX1 locus in mutant iPSC-CMs. In agreement, DNA fluorescence in situ hybridization (FISH) revealed that the PRRX1 locus loses peripheral association and relocates towards the transcriptionally active nuclear interior in mutant iPSC-CMs. Correspondingly, single-cell assay for transposase accessible chromatin (ATAC)-seq showed increased chromatin co-accessibility at the PRRX1 locus, providing a plausible explanation for ectopic activation of PRRX1 in LMNA mutant iPSC-CMs. Conclusion: Our data suggest that LMNA haploinsufficiency disrupts the structure of LADs, leading to ectopic promoter interactions and altered gene expression in LMNA -related DCM iPSC-CMs. We identified PRRX1 as a promising candidate locus linking changes in LAD organization with gene dysregulation in LMNA -related DCM.

scholarly journals Stable transfer and restricted expression of a cloned class I gene encoding a secreted transplantation-like antigen.

1985 ◽  
Vol 5 (6) ◽  
pp. 1295-1300 ◽  
Author(s):  
Y Barra ◽  
K Tanaka ◽  
K J Isselbacher ◽  
G Khoury ◽  
G Jay
Keyword(s):  
Molecular Mechanisms ◽  
Cell Types ◽  
Class I ◽  
Regulatory Sequences ◽  
Transcriptional Enhancer ◽  
Gene Encoding ◽  
Specific Expression ◽  
Tissue Specific ◽  
Functional Studies ◽  
I Gene

The identification of a unique major histocompatibility complex class I gene, designated Q10, which encodes a secreted rather than a cell surface antigen has led to questions regarding its potential role in regulating immunological functions. Since the Q10 gene is specifically activated only in the liver, we sought to define the molecular mechanisms which control its expression in a tissue-specific fashion. Results obtained by transfection of the cloned Q10 gene, either in the absence or presence of a heterologous transcriptional enhancer, into a variety of cell types of different tissue derivations are consistent with the Q10 gene being regulated at two levels. The first is by a cis-dependent mechanism which appears to involve site-specific DNA methylation. The second is by a trans-acting mechanism which would include the possibility of an enhancer binding factor. The ability to efficiently express the Q10 gene in certain transfected cell lines offers an opportunity to obtain this secreted class I antigen in quantities sufficient for functional studies; this should also make it possible to define regulatory sequences which may be responsible for the tissue-specific expression of Q10.

scholarly journals Three tightly linked genes encoding human type I keratins: conservation of sequence in the 5'-untranslated leader and 5'-upstream regions of coexpressed keratin genes.

1986 ◽  
Vol 6 (2) ◽  
pp. 539-548 ◽  
Author(s):  
A RayChaudhury ◽  
D Marchuk ◽  
M Lindhurst ◽  
E Fuchs
Keyword(s):  
Molecular Mechanisms ◽  
Type I ◽  
Differential Splicing ◽  
Gene Encoding ◽  
Linked Gene ◽  
Human Dna ◽  
Human Epidermal Cells ◽  
Genes Encoding ◽  
Positive Hybridization ◽  
Endonuclease Mapping

We have isolated and subcloned three separate segments of human DNA which share strong sequence homology with a previously sequenced gene encoding a type I keratin, K14 (50 kilodaltons). Restriction endonuclease mapping has demonstrated that these three genes are tightly linked chromosomally, whereas the K14 gene appears to be separate. As judged by positive hybridization-translation and Northern blot analyses, the central linked gene encodes a keratin, K17, which is expressed in abundance with K14 and two other type I keratins in cultured human epidermal cells. None of these other epidermal keratin mRNAs appears to be generated from the K17 gene through differential splicing of its transcript. The sequence of the K17 gene reveals striking homologies not only with the coding portions and intron positions of the K14 gene, but also with its 5'-noncoding and 5'-upstream sequences. These similarities may provide an important clue in elucidating the molecular mechanisms underlying the coexpression of the two genes.

Intracellular mechanisms involved in the regulation of vascular smooth muscle tone

1995 ◽  
Vol 73 (5) ◽  
pp. 565-573 ◽  
Author(s):  
Michael P. Walsh ◽  
Gary J. Kargacin ◽  
John Kendrick-Jones ◽  
Thomas M. Lincoln
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase ◽  
Vascular Smooth Muscle ◽  
Cyclic Gmp ◽  
Vascular Tone ◽  
Light Chains ◽  
Dependent Protein Kinase ◽  
Dependent Protein ◽  
Regulation Of Vascular Tone

Vascular smooth muscle contraction is thought to occur by a mechanism similar to that described for striated muscles, i.e., via a cross-bridge cycling – sliding filament mechanism. This symposium focused on Ca2+ signalling and the role of intracellular free Ca2+ concentration, [Ca2+]i, in regulating vascular tone: how contractile stimuli leading to an increase in [Ca2+]i trigger vasoconstriction and how relaxant signals reduce [Ca2+]i causing vasodilation. M.P. Walsh opened the symposium with an overview emphasizing the central role of myosin phosphorylation–dephosphorylation in the regulation of vascular tone and identifying recent developments concerning regulation of [Ca2+]i, Ca2+ sensitization and desensitization of the contractile response, Ca2+-independent protein kinase C induced contraction, and direct regulation of cross-bridge cycling by the thin filament associated proteins caldesmon and calponin. The remainder of the symposium focused on three specific areas related to the regulation of vascular tone: Ca2+ signalling in relation to smooth muscle structure, structure–function relations of myosin, and the role of cyclic GMP (cGMP) dependent protein kinase. G.J. Kargacin described how smooth muscle cells are structured and how second messenger signals such as Ca2+ might be modified or influenced by this structure. J. Kendrick-Jones then discussed the results of mutagenesis studies aimed at understanding how the myosin light chains, particularly the phosphorylatable (Ca2+–calmodulin dependent) regulatory light chains, control myosin. The vasorelaxant effects of signalling molecules such as β-adrenergic agents and nitrovasodilators are mediated by cyclic nucleotide dependent protein kinases, leading principally to a reduction in [Ca2+]i. T.M. Lincoln described the roles of cyclic nucleotide dependent protein kinases, in particular cyclic GMP dependent protein kinase, in vasodilation.Key words: vascular smooth muscle, regulation of contraction, smooth muscle structure, calcium, cyclic GMP, myosin.

scholarly journals Activins regulate 17β-hydroxysteroid dehydrogenase type I transcription in murine gonadotrope cells

2009 ◽  
Vol 201 (1) ◽  
pp. 89-104 ◽  
Author(s):  
Beata Bak ◽  
Laura Carpio ◽  
Jinjing L Kipp ◽  
Pankaj Lamba ◽  
Ying Wang ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Intracellular Signaling ◽  
Cell Types ◽  
Hydroxysteroid Dehydrogenase ◽  
Activin A ◽  
Type I ◽  
Promoter Regions ◽  
Gene Encoding ◽  
17Β Estradiol ◽  
Smad Binding Element

Activins are pleiotropic members of the TGFβ superfamily and were initially characterized based on their abilities to stimulate FSH synthesis and secretion by gonadotrope cells of the anterior pituitary gland. Here, we identified the gene encoding the steroidogenic enzyme, 17β-hydroxysteroid dehydrogenase type I (17β-HSD1; Hsd17b1), as an activin-responsive gene in immortalized gonadotrope cells, LβT2. 17β-HSD1 catalyzes the conversion of estrone to the more active 17β-estradiol, and activin A stimulated an increase in this enzymatic activity in these cells. We demonstrated that activins signaled via the type I receptor, activin receptor-like kinase (ALK4), and the intracellular signaling protein, SMAD2, to regulate Hsd17b1 transcription in immediate-early fashion. Critical cis-elements, including a minimal SMAD-binding element, were mapped to within 100 bp of the start of transcription. Activin/ALK4 signaling also regulated Hsd17b1 transcription in both immortalized and primary cultured murine granulosa cells. The promoter regions mediating basal and activin/ALK4-regulated promoter activity were generally conserved across the different cell types. The data show that activin A rapidly regulates Hsd17b1 transcription in gonadotrope and granulosa cells and may thereby regulate local 17β-estradiol synthesis.

scholarly journals Profiling of Primary and Mature miRNA Expression in Atherosclerosis Associated Cell Types

2021 ◽  
Author(s):  
Pierre R. Moreau ◽  
Vanesa Tomas Bosch ◽  
Maria Bouvy-Liivrand ◽  
Kadri Õunap ◽  
Tiit Örd ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Smooth Muscle ◽  
Molecular Mechanisms ◽  
Umbilical Vein ◽  
Cell Types ◽  
Integrative Approach ◽  
Dependent Manner ◽  
Cell Type ◽  
A Cell ◽  
Cell Type Specific

Objective: Atherosclerosis is the underlying cause of most cardiovascular diseases. The main cell types associated with disease progression in the vascular wall are endothelial cells, smooth muscle cells, and macrophages. Although their role in atherogenesis has been extensively described, molecular mechanisms underlying gene expression changes remain unknown. The objective of this study was to characterize microRNA (miRNA)-related regulatory mechanisms taking place in the aorta during atherosclerosis: Approach and Results: We analyzed the changes in primary human aortic endothelial cells and human umbilical vein endothelial cell, human aortic smooth muscle cell, and macrophages (CD14+) under various proatherogenic stimuli by integrating GRO-seq, miRNA-seq, and RNA-seq data. Despite the highly cell-type-specific expression of multi-variant pri-miRNAs, the majority of mature miRNAs were found to be common to all cell types and dominated by 2 to 5 abundant miRNA species. We demonstrate that transcription contributes significantly to the mature miRNA levels although this is dependent on miRNA stability. An analysis of miRNA effects in relation to target mRNA pools highlighted pathways and targets through which miRNAs could affect atherogenesis in a cell-type-dependent manner. Finally, we validate miR-100-5p as a cell-type specific regulator of inflammatory and HIPPO-YAP/TAZ-pathways. Conclusions: This integrative approach allowed us to characterize miRNA dynamics in response to a proatherogenic stimulus and identify potential mechanisms by which miRNAs affect atherogenesis in a cell-type-specific manner.

scholarly journals L-Arginine/Nitric Oxide Pathway and KCa Channels in Endothelial Cells: A Mini-Review

2020 ◽  
Author(s):  
Marcelo González ◽  
José Carlos Rivas
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Endothelial Function ◽  
Vascular Tone ◽  
Molecular Mechanisms ◽  
Cardiovascular Health ◽  
Kca Channels ◽  
Subsequent Activation ◽  
Regulation Of Vascular Tone

The endothelium is an organ with a key role in the maintenance of cardiovascular health through the regulation of vascular tone, vascular resistance, blood flow, and arterial pressure. These functions are related with the synthesis and release of vasoactive molecules, mainly vasodilators like nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF). Both factors are released and diffused from endothelial cells to the smooth muscle cells, where there is a subsequent activation of signaling pathways that finally decrease the intracellular calcium to induce the vascular relaxation. The study of the molecular mechanisms that underlie the endothelial function still is in development, but from the evidence obtained from the endothelial cells in vitro studies are possible to partially describe the pathways to regulate the physiological endothelial function and the disturbances in pathological conditions. In this mini-review, we describe the main mechanisms for NO synthesis and the role of potassium channels related with EDHF. We include schemes and graphical summaries for better understanding of the molecular regulation of vascular tone in the human cardiovascular system.

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