Cell Proliferation In Atherosclerosis Research Articles

Exploring the anti-atherosclerosis mechanism of ginsenoside Rb1 by integrating network pharmacology and experimental verification.

Ginsenoside Rb1 is the major active constituent of ginseng, which is widely used in traditional Chinese medicine for the atherosclerosis treatment by anti-inflammatory, anti-oxidant and reducing lipid accumulation. We explored cellular target and molecular mechanisms of ginsenoside Rb1 based on network pharmacology and in vitro experimental validation. In this study, we predicted 17 potential therapeutic targets for ginsenoside Rb1 with atherosclerosis from public databases. We then used protein-protein interaction network to screen the hub targets. Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway enrichment showed that the effects of ginsenoside Rb1 were meditated through multiple targets and pathways. Next, molecular docking results revealed that in the 10 core targets, CCND1 has the highest binding energy with ginsenoside Rb1. Vascular cell proliferation plays a critical role in atherosclerosis development. However, the effect and direct target of ginsenoside Rb1 in regulating vascular cell proliferation in atherosclerosis remains unclear. Edu straining results indicated that ginsenoside Rb1 inhibited the cell proliferation of endothelial cells, macrophages, and vascular smooth muscle cells. The protein immunoprecipitation (IP) analysis showed that ginsenoside Rb1 inhibited the vascular cell proliferation by suppressing the interaction of CCDN1 and CDK4. These findings systematically reveal that the anti-atherosclerosis mechanism of ginsenoside Rb1 by integrating network pharmacology and experimental validation, which provide evidence to treat atherosclerosis by using ginsenoside Rb1 and targeting CCND1.

Retraction notice: "Long noncoding RNA SNHG14 regulates ox-LDL-induced atherosclerosis cell proliferation and apoptosis by targeting miR-186-5p/WIPF2 axis".

Retraction notice: "Long noncoding RNA SNHG14 regulates ox-LDL-induced atherosclerosis cell proliferation and apoptosis by targeting miR-186-5p/WIPF2 axis".

Infection makes micro-CHIPs into macro-CHIPs.

In this issue of Cell Stem Cell, Hormaechea-Agulla etal. (2021) demonstrate that IFNγ signaling following an infection in mice provides a selective pressure that drives growth of Dnmt3a-/- hematopoietic stem cells. This clonal expansion is mediated by global methylation changes that lead to an increased self-renewing capacity.

Long noncoding RNA SNHG14 regulates ox-LDL-induced atherosclerosis cell proliferation and apoptosis by targeting miR-186-5p/WIPF2 axis.

To investigate the role of small nucleolus RNA host gene 14 (SNHG14) in the progression of atherosclerosis (AS), bioinformatics analysis, and other relevant experiments (cell counting kit-8, flow cytometry, quantitative real-time polymerase chain reaction, luciferase reporter, RNA immunoprecipitation, RNA pull-down, and western blot assays) were done. The current study revealed that SNHG14 level was high in the serum of AS patients and oxidized low-density lipoprotein (ox-LDL)-induced AS cell lines. Besides, we found that SNHG14 accelerated cell proliferation while inhibited cell apoptosis in ox-LDL-induced AS cell lines. Next, SNHG14 was confirmed to be a sponge for miR-186-5p in AS cells, and it was validated that SNHG14 regulated AS cell proliferation and apoptosis by sponging miR-186-5p. Moreover, we uncovered that WAS-interacting protein family member 2 (WIPF2) was a downstream target of miR-186-5p in AS cells. Finally, it was demonstrated that miR-186-5p modulated AS cell proliferation and apoptosis via targeting WIPF2. To conclude, our research disclosed that SNHG14 affected ox-LDL-induced AS cell proliferation and apoptosis through miR-186-5p/WIPF2 axis, which may provide a theoretical basis for the treatment and diagnosis of AS.

Functional Validation of a Common Nonsynonymous Coding Variant in ZC3HC1 Associated With Protection From Coronary Artery Disease.

Although virtually all coronary artery disease associated single-nucleotide polymorphisms identified by genome-wide association studies (GWAS) are in noncoding regions of the genome, a common polymorphism in ZC3HC1 (rs11556924), resulting in an arginine (Arg) to histidine (His) substitution in its encoded protein, NIPA (Nuclear Interacting Partner of Anaplastic Lyphoma Kinase) is linked to a protection from coronary artery disease. NIPA plays a role in cell cycle progression, but the functional consequences of this polymorphism have not been established. Here we demonstrate that total ZC3HC1 expression in whole blood is similar across genotypes, despite expression being slightly biased toward the risk allele in heterozygotes. At the protein level, the protective His363 NIPA variant exhibits increased phosphorylation of a critical serine residue (Ser354) and higher protein expression as compared with the Arg363 variant. Binding experiments indicate that neither SKP1 (S-phase kinase-associated protein 1) nor CCNB1 binding were affected by the polymorphism. Despite similar nuclear distribution, NIPA His363 exhibits greater nuclear mobility. NIPA suppression results in a modest reduction of proliferation in vascular smooth muscle cells, but given low proliferative capacity, a significant effect of the variant was not noted. By contrast, we demonstrate that the protective variant reduces cell proliferation in HeLa cells. These findings extend the genetic association between rs11556924 and coronary artery disease risk by characterizing its effects on the encoded protein, NIPA. The resulting amino acid change Arg363His is associated with increased expression and nuclear mobility, as well as lower rates of cell growth in HeLa cells, further supporting a role for cell proliferation in atherosclerosis and its clinical consequences.

Imaging Macrophage and Hematopoietic Progenitor Proliferation in Atherosclerosis.

Local plaque macrophage proliferation and monocyte production in hematopoietic organs promote progression of atherosclerosis. Therefore, noninvasive imaging of proliferation could serve as a biomarker and monitor therapeutic intervention. To explore (18)F-FLT positron emission tomography-computed tomography imaging of cell proliferation in atherosclerosis. (18)F-FLT positron emission tomography-computed tomography was performed in mice, rabbits, and humans with atherosclerosis. In apolipoprotein E knock out mice, increased (18)F-FLT signal was observed in atherosclerotic lesions, spleen, and bone marrow (standardized uptake values wild-type versus apolipoprotein E knock out mice, 0.05 ± 0.01 versus 0.17 ± 0.01, P<0.05 in aorta; 0.13 ± 0.01 versus 0.28 ± 0.02, P<0.05 in bone marrow; 0.06 ± 0.01 versus 0.22 ± 0.01, P<0.05 in spleen), corroborated by ex vivo scintillation counting and autoradiography. Flow cytometry confirmed significantly higher proliferation of macrophages in aortic lesions and hematopoietic stem and progenitor cells in the spleen and bone marrow in these mice. In addition, (18)F-FLT plaque signal correlated with the duration of high cholesterol diet (r(2)=0.33, P<0.05). Aortic (18)F-FLT uptake was reduced when cell proliferation was suppressed with fluorouracil in apolipoprotein E knock out mice (P<0.05). In rabbits, inflamed atherosclerotic vasculature with the highest (18)F-fluorodeoxyglucose uptake enriched (18)F-FLT. In patients with atherosclerosis, (18)F-FLT signal significantly increased in the inflamed carotid artery and in the aorta. (18)F-FLT positron emission tomography imaging may serve as an imaging biomarker for cell proliferation in plaque and hematopoietic activity in individuals with atherosclerosis.

In This Issue

HomeCirculation ResearchVol. 116, No. 11In This Issue Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBIn This Issue Ruth Williams Ruth WilliamsRuth Williams Search for more papers by this author Originally published22 May 2015https://doi.org/10.1161/RES.0000000000000058Circulation Research. 2015;116:1725CHOP Regulates Smooth Muscle Cell Proliferation (p 1736)Download figureDownload PowerPointCHOP protein promotes vascular smooth muscle cell proliferation in atherosclerosis, report Zhou et al.Atherosclerotic plaques are characterized by high levels of inflammation, macrophage infiltration and abnormal smooth muscle cell proliferation. Moreover, both human and mouse plaques exhibit symptoms of chronic endoplasmic reticulum (ER) stress, including prolonged increase in the expression of C/EBP homologous protein (CHOP). Chronically elevated levels of CHOP promote macrophage apoptosis and associated plaque necrosis. However, it is not clear whether CHOP affects the other major cellular component of plaques—vascular smooth muscle cells (VSMCs). Therefore to test the role of CHOP in smooth muscle cells, Zhou and colleagues specifically depleted CHOP from VSMCs in atherosclerosis-prone mice. They found that in these mice, plaques were approximately 30 percent smaller and that the number of VSMCs were significantly reduced—even after correcting for decreased plaque size. They also found that CHOP-deficient VSMCs expressed greater levels of the protein KLF4—an inhibitor of VSMC proliferation. KLF4 expression was increased both by transcriptional upregulation and by reduced degradation of the protein itself. These finding suggest that CHOP promotes the progression of atherosclerosis in at least two ways—macrophage apoptosis and VSMC proliferation—making it a potential target for future anti-atherosclerotic therapies.miR-143/145 Modulates EC Biology (p 1753)Download figureDownload PowerPointCliment et al discover that smooth muscle cells control endothelial cell function via microRNA transfer.MicroRNAs (miRs) are short, non-coding RNAs that bind and inhibit expression of target mRNAs. Recent evidence has also revealed that miRs can act as communication signals, being released by cells to exert effects on their neighbors. In vascular smooth muscle cells (VSMCs), the two miRs, miR143 and miR145, are critical controllers of both differentiation and switching of phenotype to a proliferative state. Climent and colleagues have now examined whether these SMC-derived miRs might also effect neighboring endothelial cells (ECs). In agreement with previous suggestions, they found that the miRs are transferred from SMCs to ECs in co-culture—most likely via membrane protusions called tunneling nanotubes. The transferred miRs suppressed angiogenic potential of the ECs, impairing the ability of these cells to form capillary-like structures in culture. The team also showed that the transfer of miR143 and 145 was induced by TGFβ—which promotes VSMC differentiation and vessel stabilization. Finally, they confirmed that SMC-to-EC transfer of the miRs also occurred in live mice. Together the results highlight the role of miR143 and 145 as important anti-angiogenic signals that could be useful targets for future pro- or anti-angiogenic therapies.Post-MI Vascular Endocardial Remodeling (p 1765)Download figureDownload PowerPointBlooms of arterial endothelial cells emerge from the heart’s endocardium after an infarction, according to research by Miquerol et al.Revascularization is an important prerequisite for ischemic tissue to survive after myocardial infarction. However, innate revascularization ability is limited. Strategies to therapeutically boost revascularization are thus the focus of intense research, but so far have met only limited success. To learn more about this process, Miquerol and colleagues turned their attention to the endocardium because recent evidence suggests that during embryogenesis, coronary vessels originate from this tissue. They found that after myocardial infarction, the endocardium provided a source of new vessel endothelial cells in adult mice. Three to seven days after the infarction, bursts of new arterial endothelial cells, which formed structures described by the authors as endocardial flowers, were apparent within the endocardium. Analyses revealed that these flowers were indeed endocardial in origin, were connected to coronary artery fistulae (or stems) and gradually acquired the expression of endothelial markers. Determining the molecular mechanisms that control the endocardial to endothelial fate switch will likely be important for optimizing therapeutic revascularization strategies, say the authors. Previous Back to top Next FiguresReferencesRelatedDetails May 22, 2015Vol 116, Issue 11 Advertisement Article InformationMetrics © 2015 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000058 Originally publishedMay 22, 2015 PDF download Advertisement

Control of cell proliferation in atherosclerosis: insights from animal models and human studies

Excessive hyperplastic cell growth within occlusive vascular lesions has been recognized as a key component of the inflammatory response associated with atherosclerosis, restenosis post-angioplasty, and graft atherosclerosis after coronary artery bypass. Understanding the molecular mechanisms that regulate arterial cell proliferation is therefore essential for the development of new tools for the treatment of these diseases. Mammalian cell proliferation is controlled by a large number of proteins that modulate the mitotic cell cycle, including cyclin-dependent kinases, cyclins, and tumour suppressors. The purpose of this review is to summarize current knowledge about the role of these cell cycle regulators in the development of native and graft atherosclerosis that has arisen from animal studies, histological examination of specimens from human patients, and genetic studies.

DNA Methylation and Atherosclerosis

DNA methylation is a major epigenetic modification of the genome that has the potential to silence gene expression. Recently, the role of epigenetic alteration as a distinct and crucial mechanism to regulate genes governing cell proliferation in atherosclerosis has emerged. Aberrant methylation is related to aging, and, because it affects a large number of CpG islands, age-related methylation may be an important contributor to increased atherosclerosis among older individuals by upregulating atherosclerosis-susceptible genes and downregulating atherosclerosis-protective genes. Further dissection of epigenetic alterations in atherosclerosis and aging will lead to the identification of novel epigenetic modifiers and improved diagnosis and treatment for atherosclerosis-related diseases.

β-Migrating Very Low Density Lipoprotein (βVLDL) Activates Smooth Muscle Cell Mitogen-activated Protein (MAP) Kinase via G Protein-coupled Receptor-mediated Transactivation of the Epidermal Growth Factor (EGF) Receptor: EFFECT OF MAP KINASE ACTIVATION ON βVLDL PLUS EGF-INDUCED CELL PROLIFERATION

This study examined the premise that the atherogenic lipoprotein, beta-migrating very low density lipoprotein (betaVLDL), might activate the mitogen-activated protein (MAP) kinases ERK1/ERK2, thereby contributing to the induction of smooth muscle cell proliferation in atherosclerosis. The data show that betaVLDL activates rabbit smooth muscle cell ERK1/ERK2. Interestingly, ERK1/ERK2 activation is mediated by G protein-coupled receptors that transactivate the epidermal growth factor (EGF) receptor. betaVLDL-induced MAP kinase activation depends on Ras and Src activity as well as protein kinase C. The inhibition of lysosomal degradation of betaVLDL has no effect on ERK1/ERK2 activation. The contribution of betaVLDL-induced activation of ERK1/ERK2 to smooth muscle cell proliferation was also explored. betaVLDL induces expression of egr-1 and c-fos mRNA. Despite its ability to stimulate early gene expression, betaVLDL alone is unable to inspire quiescent cells into S phase. When added in conjunction with EGF, however, stimulation of [(3)H]thymidine incorporation into DNA and an increase in histone gene expression are observed. Moreover, betaVLDL plus EGF synergistically induce cyclin D1 expression and down-regulate p27(KIP1) expression. The addition of either betaVLDL or EGF stimulates a robust activation of ERK1/ERK2, but the addition of both agents simultaneously sustains the activation for a longer time period. Inhibition of MAP kinase kinase, pertussis toxin-sensitive G proteins, the EGF receptor, or protein kinase C blocks betaVLDL plus EGF-induced proliferation, demonstrating that activation of the betaVLDL-induced signaling pathway results in smooth muscle cell proliferation.

Trends in Cardiovascular Medicine

<i>Trends in Cardiovascular Medicine</i>publishes concise reports on recent developments across a broad range of cardiovascular research. "Emerging Techniques"—a regular feature—focuses on new diagnostic tools and potential clinical applications. In the journal's first issue, this section contained provocative articles on the role of the polymerase chain reaction for cardiovascular diagnoses and on the feasibility, safety, and utility of percutaneous coronary angioscopy. A "Brief Reviews" section offers short (six-page) articles covering such diverse topics as cell proliferation in atherosclerosis, lipid abnormalities in myocardial cell injury, and the use of molecular mutants and biochemical conjugates in thrombolytic therapy. "Gene Transfer and Cardiovascular Disease" by Elizabeth G. Nabel and Gary J. Nabel is the sort of clearly written distillation of scientific research more often found in the pages of<i>Science</i>or<i>Nature</i>than in a specialized medical journal. (Indeed, two earlier reports on this subject by the same authors did appear in<i>Science</i>

Cellular proliferation in atherosclerosis and hypertension.

Cell proliferation is now recognized as a common feature of the vascular response to injury characteristic of both hypertension and atherosclerosis. Our concepts of the role of proliferation in the underlying mechanisms for each disease, however, have been entirely different.Current concepts about atherosclerosis began with the work of Virchow. He recognized the presence of cell proliferation in atherosclerosis over a century ago but viewed the cellular events as reactive rather than etiologic (1). This view has changed over the last two decades. With the development of the electron microscope, pathologists were able to identify the smooth muscle cell as the characteristic cell of the atherosclerotic plaque. A number of manipulations, including removal of the endothelium and exposure of the animals to hyperlipemia were shown to result in smooth muscle proliferation. These studies in animals and in humans support the idea that the initial step in lesion formation, prior to increase in intimal lipids, is th...

Population dynamics of arterial cells during atherogenesis: VII. Comparison of loss of endothelial cells over abdominal aortic intimal cellular masses (ICM) with that over non-ICM areas in swine fed a hyperlipidemic diet for 60 days

One of the earlies events in the development of an intimal atherosclerotic lesion may be an alteration in the endothelial cell barrier, allowing the entry of injurious or mitogenic substances, resulting in proliferation of arterial smooth muscle cells. Intimal smooth muscle cell proliferation in atherosclerosis appears to begin in intimal cellular masses (ICM), which are normally occurring intimal structures made up of 2 to 10 layers of smooth muscle cells found predominantly in relation to branching points of arteries. If endothelial cell loss is a precursor of overt atherosclerotic lesions, the loss should be greater over ICM than over areas showing no ICM. This study presents evidence suggesting that in swine the endothelial cell barrier is compromised over intimal cell masses more than in non-ICM regions prior to development of overt atherosclerotic lesions. The method used was to label swine aortic endothelium and ICM using tritiated thymidine. All swine were then placed on a low-fat, low-cholesterol diet for 15 days, at which time five baseline animals were sacrificed; the remaining five were placed on a hyperlipidemic (HL) diet and sacrificed 60 days later. The rate of endothelial cell growth, division patterns, and loss of labeled endothelial cells in the HL swine was determined by comparing the findings in this group with the baseline group. Smooth muscle cells of ICM and non-ICM medial regions were similar in regard to labeling indices in the baseline swine and in regard to division patterns in 60-day HL diet swine, except one which was an active lesion. None of the remaining ICM were active lesions and thus were suitable for study of the covering endothelial cells in what can be assumed to be the prodromal stage of lesion development. The approximate area of the abdominal aorta occupied by intimal cell mass was considerably more than we had anticipated, averaging more than 20%. The labeling indices and endothelial cell division patterns over ICM and non-ICM in the baseline swine were similar. In contrast, the labeling index was lower, and grain count changes indicated more endothelial cell divisions over ICM areas than over non-ICM areas in the hypercholesterolemic swine. Calculation showed that the percentage of endothelial cell loss over ICM in the HL swine was more than twice as great as endothelial cell loss over non-ICM areas. The results of this study suggest the possibility that in the assumed prodromal phase of experimental aortic atherosclerosis in young swine, the endothelial cell barrier may be compromised selectively over areas of predilection for the future development of atherosclerotic lesions. This occurs before there is any evidence of focal increase in intimal smooth muscle cell proliferation, which we regard as the earliest detectable stage of lesion development.

Proliferation of arterial cells in atherosclerosis.

The role of cell proliferation in atherosclerosis has received much attention. It has been suggested for many years that the increase in cells during the formation of intimal lesions may be due to intrinsic proliferation. This hypothesis was based mainly on the observation of mitotic figures in the smooth muscle and foam cells of atherosclerotic plaques, even though mitoses were seen only rarely. On the other hand, it was proposed but never definitely established that migration of cells from the circulation, endothelium or media accounts for the cellular growth of the lesions. Monocytes, endothelial cells, and medial smooth muscle cells thus have been implicated.