scholarly journals Molecular and Cellular Mechanisms Driving Cardiovascular Disease in Hutchinson-Gilford Progeria Syndrome: Lessons Learned from Animal Models

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1157
Author(s):  
Ignacio Benedicto ◽  
Beatriz Dorado ◽  
Vicente Andrés
Keyword(s):  
Cardiovascular Disease ◽  
Animal Models ◽  
Current Knowledge ◽  
Life Quality ◽  
Cell Loss ◽  
Cell Types ◽  
Lessons Learned ◽  
Cellular Mechanisms ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease that recapitulates many symptoms of physiological aging and precipitates death. Patients develop severe vascular alterations, mainly massive vascular smooth muscle cell loss, vessel stiffening, calcification, fibrosis, and generalized atherosclerosis, as well as electrical, structural, and functional anomalies in the heart. As a result, most HGPS patients die of myocardial infarction, heart failure, or stroke typically during the first or second decade of life. No cure exists for HGPS, and therefore it is of the utmost importance to define the mechanisms that control disease progression in order to develop new treatments to improve the life quality of patients and extend their lifespan. Since the discovery of the HGPS-causing mutation, several animal models have been generated to study multiple aspects of the syndrome and to analyze the contribution of different cell types to the acquisition of the HGPS-associated cardiovascular phenotype. This review discusses current knowledge about cardiovascular features in HGPS patients and animal models and the molecular and cellular mechanisms through which progerin causes cardiovascular disease.

scholarly journals The Biology Underlying Abnormalities of Tooth Number in Humans

2017 ◽  
Vol 96 (11) ◽  
pp. 1248-1256 ◽  
Author(s):  
E. Juuri ◽  
A. Balic
Keyword(s):  
Animal Models ◽  
Signaling Pathways ◽  
Tooth Development ◽  
Current Knowledge ◽  
Tooth Agenesis ◽  
Cellular Mechanisms ◽  
Tooth Shape ◽  
Tooth Abnormalities ◽  
Tooth Number ◽  
The Common

In past decades, morphologic, molecular, and cellular mechanisms that govern tooth development have been extensively studied. These studies demonstrated that the same signaling pathways regulate development of the primary and successional teeth. Mutations of these pathways lead to abnormalities in tooth development and number, including aberrant tooth shape, tooth agenesis, and formation of extra teeth. Here, we summarize the current knowledge on the development of the primary and successional teeth in animal models and describe some of the common tooth abnormalities in humans.

scholarly journals Molecular and Cellular Mechanisms Modulating Trained Immunity by Various Cell Types in Response to Pathogen Encounter

2021 ◽  
Vol 12 ◽  
Author(s):  
Orlando A. Acevedo ◽  
Roslye V. Berrios ◽  
Linmar Rodríguez-Guilarte ◽  
Bastián Lillo-Dapremont ◽  
Alexis M. Kalergis
Keyword(s):  
Immune Cells ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Tca Cycle ◽  
Cell Types ◽  
Innate Immune ◽  
Epigenetic Changes ◽  
Cellular Mechanisms ◽  
Functional Changes ◽  
Trained Immunity

The induction of trained immunity represents an emerging concept defined as the ability of innate immune cells to acquire a memory phenotype, which is a typical hallmark of the adaptive response. Key points modulated during the establishment of trained immunity include epigenetic, metabolic and functional changes in different innate-immune and non-immune cells. Regarding to epigenetic changes, it has been described that long non-coding RNAs (LncRNAs) act as molecular scaffolds to allow the assembly of chromatin-remodeling complexes that catalyze epigenetic changes on chromatin. On the other hand, relevant metabolic changes that occur during this process include increased glycolytic rate and the accumulation of metabolites from the tricarboxylic acid (TCA) cycle, which subsequently regulate the activity of histone-modifying enzymes that ultimately drive epigenetic changes. Functional consequences of established trained immunity include enhanced cytokine production, increased antigen presentation and augmented antimicrobial responses. In this article, we will discuss the current knowledge regarding the ability of different cell subsets to acquire a trained immune phenotype and the molecular mechanisms involved in triggering such a response. This knowledge will be helpful for the development of broad-spectrum therapies against infectious diseases based on the modulation of epigenetic and metabolic cues regulating the development of trained immunity.

Novel potential targets for prevention of arterial restenosis: insights from the pre-clinical research

2014 ◽  
Vol 127 (11) ◽  
pp. 615-634 ◽  
Author(s):  
Amalia Forte ◽  
Barbara Rinaldi ◽  
Liberato Berrino ◽  
Francesco Rossi ◽  
Umberto Galderisi ◽  
...  
Keyword(s):  
Animal Models ◽  
Bypass Graft ◽  
Bare Metal Stents ◽  
Cell Types ◽  
Experimental Models ◽  
Metal Stents ◽  
Cellular Mechanisms ◽  
Pathophysiological Process ◽  
Drug Eluting ◽  
Revascularization Procedures

Restenosis is the pathophysiological process occurring in 10–15% of patients submitted to revascularization procedures of coronary, carotid and peripheral arteries. It can be considered as an excessive healing reaction of the vascular wall subjected to arterial/venous bypass graft interposition, endarterectomy or angioplasty. The advent of bare metal stents, drug-eluting stents and of the more recent drug-eluting balloons, have significantly reduced, but not eliminated, the incidence of restenosis, which remains a clinically relevant problem. Biomedical research in pre-clinical animal models of (re)stenosis, despite its limitations, has contributed enormously to the identification of processes involved in restenosis progression, going well beyond the initial dogma of a primarily proliferative disease. Although the main molecular and cellular mechanisms underlying restenosis have been well described, new signalling molecules and cell types controlling the progress of restenosis are continuously being discovered. In particular, microRNAs and vascular progenitor cells have recently been shown to play a key role in this pathophysiological process. In addition, the advanced highly sensitive high-throughput analyses of molecular alterations at the transcriptome, proteome and metabolome levels occurring in injured vessels in animal models of disease and in human specimens serve as a basis to identify novel potential therapeutic targets for restenosis. Molecular analyses are also contributing to the identification of reliable circulating biomarkers predictive of post-interventional restenosis in patients, which could be potentially helpful in the establishment of an early diagnosis and therapy. The present review summarizes the most recent and promising therapeutic strategies identified in experimental models of (re)stenosis and potentially translatable to patients subjected to revascularization procedures.

scholarly journals MicroRNAs as Therapeutic Targets and Clinical Biomarkers in Atherosclerosis

2019 ◽  
Vol 8 (12) ◽  
pp. 2199 ◽  
Author(s):  
Emma L. Solly ◽  
Catherine G. Dimasi ◽  
Christina A. Bursill ◽  
Peter J. Psaltis ◽  
Joanne T. M. Tan
Keyword(s):  
Cardiovascular Disease ◽  
Therapeutic Targets ◽  
Holistic Approach ◽  
Cell Types ◽  
Atherosclerotic Cardiovascular Disease ◽  
Cellular Mechanisms ◽  
Cellular Effects ◽  
Clinical Biomarkers ◽  
Current Therapies ◽  
Multiple Cell

Atherosclerotic cardiovascular disease remains the leading cause of morbidity and mortality worldwide. Atherosclerosis develops over several decades and is mediated by a complex interplay of cellular mechanisms that drive a chronic inflammatory milieu and cell-to-cell interactions between endothelial cells, smooth muscle cells and macrophages that promote plaque development and progression. While there has been significant therapeutic advancement, there remains a gap where novel therapeutic approaches can complement current therapies to provide a holistic approach for treating atherosclerosis to orchestrate the regulation of complex signalling networks across multiple cell types and different stages of disease progression. MicroRNAs (miRNAs) are emerging as important post-transcriptional regulators of a suite of molecular signalling pathways and pathophysiological cellular effects. Furthermore, circulating miRNAs have emerged as a new class of disease biomarkers to better inform clinical diagnosis and provide new avenues for personalised therapies. This review focusses on recent insights into the potential role of miRNAs both as therapeutic targets in the regulation of the most influential processes that govern atherosclerosis and as clinical biomarkers that may be reflective of disease severity, highlighting the potential theranostic (therapeutic and diagnostic) properties of miRNAs in the management of cardiovascular disease.

scholarly journals Vascular Smooth Muscle Cell-Specific Progerin Expression Provokes Contractile Impairment in a Mouse Model of Hutchinson-Gilford Progeria Syndrome that Is Ameliorated by Nitrite Treatment

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 656 ◽  
Author(s):  
Lara del Campo ◽  
Amanda Sánchez-López ◽  
Cristina González-Gómez ◽  
María Jesús Andrés-Manzano ◽  
Beatriz Dorado ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Endothelial Dysfunction ◽  
Mouse Model ◽  
Vascular Smooth Muscle ◽  
Vascular Tone ◽  
Genetic Disorder ◽  
Cell Types ◽  
Dietary Sodium ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Cardiovascular disease (CVD) is the main cause of death worldwide, and aging is its leading risk factor. Aging is much accelerated in Hutchinson–Gilford progeria syndrome (HGPS), an ultra-rare genetic disorder provoked by the ubiquitous expression of a mutant protein called progerin. HGPS patients die in their teens, primarily due to cardiovascular complications. The primary causes of age-associated CVD are endothelial dysfunction and dysregulated vascular tone; however, their contribution to progerin-induced CVD remains poorly characterized. In the present study, we found that progeroid LmnaG609G/G609G mice with ubiquitous progerin expression show both endothelial dysfunction and severe contractile impairment. To assess the relative contribution of specific vascular cell types to these anomalies, we examined LmnaLCS/LCSTie2Cretg/+ and LmnaLCS/LCSSm22αCretg/+ mice, which express progerin specifically in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), respectively. Whereas vessel contraction was impaired in mice with VSMC-specific progerin expression, we observed no endothelial dysfunction in mice with progerin expression restricted to VSMCs or ECs. Vascular tone regulation in progeroid mice was ameliorated by dietary sodium nitrite supplementation. Our results identify VSMCs as the main cell type causing contractile impairment in a mouse model of HGPS that is ameliorated by nitrite treatment.

scholarly journals Hutchinson-Gilford Progeria Syndrome—Current Status and Prospects for Gene Therapy Treatment

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 88 ◽  
Author(s):  
Katarzyna Piekarowicz ◽  
Magdalena Machowska ◽  
Volha Dzianisava ◽  
Ryszard Rzepecki
Keyword(s):  
Gene Therapy ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Genetic Diseases ◽  
Subcutaneous Fat ◽  
Current Status ◽  
Single Mutation ◽  
Lmna Gene ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Hutchinson-Gilford progeria syndrome (HGPS) is one of the most severe disorders among laminopathies—a heterogeneous group of genetic diseases with a molecular background based on mutations in the LMNA gene and genes coding for interacting proteins. HGPS is characterized by the presence of aging-associated symptoms, including lack of subcutaneous fat, alopecia, swollen veins, growth retardation, age spots, joint contractures, osteoporosis, cardiovascular pathology, and death due to heart attacks and strokes in childhood. LMNA codes for two major, alternatively spliced transcripts, give rise to lamin A and lamin C proteins. Mutations in the LMNA gene alone, depending on the nature and location, may result in the expression of abnormal protein or loss of protein expression and cause at least 11 disease phenotypes, differing in severity and affected tissue. LMNA gene-related HGPS is caused by a single mutation in the LMNA gene in exon 11. The mutation c.1824C > T results in activation of the cryptic donor splice site, which leads to the synthesis of progerin protein lacking 50 amino acids. The accumulation of progerin is the reason for appearance of the phenotype. In this review, we discuss current knowledge on the molecular mechanisms underlying the development of HGPS and provide a critical analysis of current research trends in this field. We also discuss the mouse models available so far, the current status of treatment of the disease, and future prospects for the development of efficient therapies, including gene therapy for HGPS.

scholarly journals The Enzymatic and Non-Enzymatic Function of Myeloperoxidase (MPO) in Inflammatory Communication

Antioxidants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 562
Author(s):  
Yulia Kargapolova ◽  
Simon Geißen ◽  
Ruiyuan Zheng ◽  
Stephan Baldus ◽  
Holger Winkels ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Blood Cells ◽  
Current Knowledge ◽  
White Blood Cells ◽  
Cell Types ◽  
Multiple Roles ◽  
Polymorphonuclear Neutrophils ◽  
Autoimmune Response ◽  
Specific Expression ◽  
Enzymatic Function

Myeloperoxidase is a signature enzyme of polymorphonuclear neutrophils in mice and humans. Being a component of circulating white blood cells, myeloperoxidase plays multiple roles in various organs and tissues and facilitates their crosstalk. Here, we describe the current knowledge on the tissue- and lineage-specific expression of myeloperoxidase, its well-studied enzymatic activity and incoherently understood non-enzymatic role in various cell types and tissues. Further, we elaborate on Myeloperoxidase (MPO) in the complex context of cardiovascular disease, innate and autoimmune response, development and progression of cancer and neurodegenerative diseases.

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