Endothelial Dysfunction in Atherosclerotic Cardiovascular Diseases and Beyond: From Mechanism to Pharmacotherapies

Pharmacological Reviews, Journal Year: 2021, Volume and Issue: 73(3), P. 924 - 967

Published: June 4, 2021

The endothelium, a cellular monolayer lining the blood vessel wall, plays critical role in maintaining multiorgan health and homeostasis. Endothelial functions include dynamic maintenance of vascular tone, angiogenesis, hemostasis, provision an antioxidant, anti-inflammatory, antithrombotic interface. Dysfunction endothelium presents with impaired endothelium-dependent vasodilation, heightened oxidative stress, chronic inflammation, leukocyte adhesion hyperpermeability, endothelial cell senescence. Recent studies have implicated altered metabolism endothelial-to-mesenchymal transition as new features dysfunction. dysfunction is regarded hallmark many diverse human panvascular diseases, including atherosclerosis, hypertension, diabetes. has also been severe coronavirus disease 2019. Many clinically used pharmacotherapies, ranging from traditional lipid-lowering drugs, antihypertensive antidiabetic drugs to proprotein convertase subtilisin/kexin type 9 inhibitors interleukin 1β monoclonal antibodies, counter part their clinical benefits. regulation by noncoding RNAs provided novel insights into these newly described regulators dysfunction, thus yielding potential therapeutic approaches. Altogether, better understanding versatile (dys)functions cells will not only deepen our comprehension diseases but accelerate effective drug discovery. In this review, we provide timely overview multiple layers function, describe consequences mechanisms identify pathways targeted therapies.

Significance Statement

was initially considered be semipermeable biomechanical barrier gatekeeper health. recent decades, deepened biological led its recognition ubiquitous tissue regulating behavior, innate immunity, cell-cell interactions, wall. cardiovascular, metabolic, emerging infectious diseases. Pharmacotherapies targeting for treatment cardiovascular other

Language: Английский

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Endothelial to Mesenchymal Transition: Role in Physiology and in the Pathogenesis of Human Diseases

Physiological Reviews, Journal Year: 2019, Volume and Issue: 99(2), P. 1281 - 1324

Published: March 13, 2019

Numerous studies have demonstrated that endothelial cells are capable of undergoing to mesenchymal transition (EndMT), a newly recognized type cellular transdifferentiation. EndMT is complex biological process in which adopt phenotype displaying typical cell morphology and functions, including the acquisition motility contractile properties. Endothelial lose expression cell-specific proteins such as CD31/platelet-endothelial adhesion molecule, von Willebrand factor, vascular-endothelial cadherin initiate genes production their encoded α-smooth muscle actin, extra domain A fibronectin, N-cadherin, vimentin, fibroblast specific protein-1, also known S100A4 protein, fibrillar I III collagens. Transforming growth factor-β1 considered main inducer. However, involves numerous molecular signaling pathways triggered modulated by multiple often redundant mechanisms depending on context physiological or pathological status cells. participates highly important embryonic development processes, well pathogenesis genetically determined acquired human diseases malignant, vascular, inflammatory, fibrotic disorders. Despite intensive investigation, many aspects remain be elucidated. The identification molecules regulatory involved discovery inhibitors should provide novel therapeutic approaches for various disorders mediated EndMT.

Language: Английский

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Endothelial to Mesenchymal Transition in Cardiovascular Disease

Journal of the American College of Cardiology, Journal Year: 2019, Volume and Issue: 73(2), P. 190 - 209

Published: Jan. 1, 2019

Endothelial to mesenchymal transition (EndMT) is a process whereby an endothelial cell undergoes series of molecular events that lead change in phenotype toward (e.g., myofibroblast, smooth muscle cell). EndMT plays fundamental role during development, and mounting evidence indicates involved adult cardiovascular diseases (CVDs), including atherosclerosis, pulmonary hypertension, valvular disease, fibroelastosis. Therefore, the targeting may hold therapeutic promise for treating CVD. However, field faces number challenges, lack precise functional definition, understanding causative pathological CVDs (versus being “bystander-phenomenon”), robust human data corroborating extent causality CVDs. Here, we review this emerging but exciting field, propose framework its systematic advancement at translational levels.

Language: Английский

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lncRNA H19 prevents endothelial–mesenchymal transition in diabetic retinopathy

Diabetologia, Journal Year: 2019, Volume and Issue: 62(3), P. 517 - 530

Published: Jan. 5, 2019

Language: Английский

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Angio-LncRs: LncRNAs that regulate angiogenesis and vascular disease

Theranostics, Journal Year: 2018, Volume and Issue: 8(13), P. 3654 - 3675

Published: Jan. 1, 2018

Long noncoding RNAs (lncRNAs) represent a large subgroup of that are longer than 200 nucleotides and have no apparent protein coding potential.They diverse functions in different biological processes by regulating chromatin remodeling or translation.This review summarizes the recent progress lncRNAs angiogenesis vascular diseases.A general overview lncRNA functional mechanisms will be introduced.A list lncRNAs, which termed "Angio-LncRs", including MALAT1, MANTIS, PUNISHER, MEG3, MIAT, SENCR GATA6-AS, discussed regarding their expression, regulation, function mechanism action angiogenesis.Implications diseases, such as atherosclerosis, hypertension, retinopathies tumor also discussed.

Language: Английский

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Insights into Biological Role of LncRNAs in Epithelial-Mesenchymal Transition

Cells, Journal Year: 2019, Volume and Issue: 8(10), P. 1178 - 1178

Published: Sept. 30, 2019

Long non-coding RNAs (lncRNAs) are versatile regulators of gene expression and play crucial roles in diverse biological processes. Epithelial-mesenchymal transition (EMT) is a cellular program that drives plasticity during embryogenesis, wound healing, malignant progression. Increasing evidence shows lncRNAs orchestrate multiple processes by modulating EMT cell types. Dysregulated can impact epithelial affecting different markers target genes have been identified. However, our understanding the landscape important far from complete. Here, we summarize recent findings on mechanisms elaborate how modulate interacting with RNA, DNA, or proteins epigenetic, transcriptional, post-transcriptional regulation. This review also highlights significant pathways may be altered lncRNAs, thereby suggesting their therapeutic potential.

Language: Английский

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Detection of RNA–DNA binding sites in long noncoding RNAs

Nucleic Acids Research, Journal Year: 2019, Volume and Issue: 47(6), P. e32 - e32

Published: Jan. 15, 2019

Long non-coding RNAs (lncRNAs) can act as scaffolds that promote the interaction of proteins, RNA, and DNA. There is increasing evidence sequence-specific interactions lncRNAs with DNA via triple-helix (triplex) formation. This process allows to recruit protein complexes specific genomic regions regulate gene expression. Here we propose a computational method called Triplex Domain Finder (TDF) detect triplexes characterize DNA-binding domains targets statistically. Case studies showed this approach known Fendrr, HOTAIR MEG3. Moreover, validated novel domain in MEG3 by genome-wide sequencing method. We used TDF perform systematic analysis triplex-forming potential relevant human cardiac differentiation. demonstrated lncRNA highest potential, GATA6-AS, forms triple helices promoter genes development. down-regulation GATA6-AS impairs GATA6 expression These data indicate unique ability our tool identify their target genes.

Language: Английский

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Prediction of Gene Expression Patterns With Generalized Linear Regression Model

Frontiers in Genetics, Journal Year: 2019, Volume and Issue: 10

Published: March 3, 2019

Cell reprogramming played important roles in medical science, such as tissue repair, organ reconstruction, disease treatment, new drug development and breeding of species. Especially, Oct4, the core pluripotency factor, a key role somatic cell through transcriptional control. However, there was no scientific description quantitative relationship between Oct4 signal intensity target gene expression currently. Therefore, generalized linear regression method constructed to predict values by applying promoter regions. Experimental data, including expression, were from eight typical genes with different stages Besides, Oct 4 analyzed proposed model. results showed that our can achieve 78% goodness fit 90% confidence, which denoted partly expression.

Language: Английский

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Angiogenic Endothelial Cell Signaling in Cardiac Hypertrophy and Heart Failure

Frontiers in Cardiovascular Medicine, Journal Year: 2019, Volume and Issue: 6

Published: March 6, 2019

Endothelial cells are, by number, one of the most abundant cell types in heart and active players cardiac physiology pathology. Coronary angiogenesis plays a vital role maintaining vascularization perfusion during physiological pathological hypertrophy. On other hand, reduction capillary density with subsequent tissue hypoxia, death interstitial fibrosis contributes to development contractile dysfunction failure, as suggested clinical well experimental evidence. Although molecular causes underlying inadequate (with respect increased oxygen energy demands hypertrophied cardiomyocyte) developing hypertrophy are incompletely understood. Research efforts over past years have discovered interesting mediators potential candidates involved this process. In review article, we will focus on vascular changes occurring transition toward failure both human disease preclinical models. We summarize recent findings transgenic mice models factors expressed released from cardiomyocytes, pericytes inflammatory paracrine (dys)regulation angiogenesis. Moreover, discuss major signaling events critical angiogenic ligands endothelial their possible disturbance hypoxia or oxidative stress. regard, particularly highlight negative regulators angiogenesis, including protein tyrosine phosphatase-1B tumor suppressor p53, how they link growth metabolic control Besides death, phenotypic conversion acquisition myofibroblast-like characteristics may also contribute fibrosis, structural correlate dysfunction. Factors secreted (dysfunctional) effects cardiomyocytes hypertrophy, contractility close vicious circle reciprocal cell-cell interactions within remodeling.

Language: Английский

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New Directions in Therapeutic Angiogenesis and Arteriogenesis in Peripheral Arterial Disease

Circulation Research, Journal Year: 2021, Volume and Issue: 128(12), P. 1944 - 1957

Published: June 10, 2021

The prevalence of peripheral arterial disease (PAD) in the United States exceeds 10 million people, and PAD is a significant cause morbidity mortality across globe. typically caused by atherosclerotic obstructions large arteries to leg(s). most common clinical consequences include pain on walking (claudication), impaired functional capacity, at rest, loss tissue integrity distal limbs that may lead lower extremity amputation. Patients with also have higher than expected rates myocardial infarction, stroke, cardiovascular death. Despite advances surgical endovascular procedures, revascularization procedures be suboptimal relieving symptoms, some patients cannot treated because comorbid conditions. In cases, obstructive conduit does not assure complete limb salvage severe microvascular disease. several decades investigational efforts, medical therapies improve perfusion are limited benefit. Whereas recent studies anticoagulant (eg, rivaroxaban) intensive lipid lowering (such as PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitors) reduced major events populations, chronic ischemia remains largely resistant therapy. Experimental approaches outcomes included administration angiogenic cytokines (either recombinant protein or gene therapy) well cell Although early angiogenesis therapy were promising, these lacked sufficient control groups larger randomized trials yet achieve This review will focus what has been learned advance for how information might novel therapeutic arteriogenesis PAD.

Language: Английский

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