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 Chemokines as Therapeutic Targets in Cardiovascular Disease

2019 ◽  
Vol 39 (4) ◽  
pp. 583-592 ◽  
Author(s):  
Heidi Noels ◽  
Christian Weber ◽  
Rory R. Koenen
Keyword(s):  
Cardiovascular Disease ◽  
Clinical Manifestations ◽  
Therapeutic Targets ◽  
Drug Approval ◽  
Atherosclerotic Cardiovascular Disease ◽  
Therapeutic Approaches ◽  
The Road ◽  
Recent Developments ◽  
The Cantos ◽  
Underlying Inflammation

With the incidence and impact of atherosclerotic cardiovascular disease and its clinical manifestations still rising, therapeutic options that target the causal mechanisms of this disorder are highly desired. Since the CANTOS trial (Canakinumab Antiinflammatory Thrombosis Outcome Study) has demonstrated that lowering inflammation can be beneficial, focusing on mechanisms underlying inflammation, for example, leukocyte recruitment, is feasible. Being key orchestrators of leukocyte trafficking, chemokines have not lost their attractiveness as therapeutic targets, despite the difficult road to drug approval thus far. Still, innovative therapeutic approaches are being developed, paving the road towards the first chemokine-based therapeutic against inflammation. In this overview, recent developments for chemokines and for the chemokine-like factor MIF (macrophage migration inhibitory factor) will be discussed.

Mechanoactivation of Wnt/β-catenin pathways in health and disease

2018 ◽  
Vol 2 (5) ◽  
pp. 701-712 ◽  
Author(s):  
Christina M. Warboys
Keyword(s):  
Cardiovascular Disease ◽  
Wnt Pathway ◽  
Mechanical Strain ◽  
Cell Types ◽  
Mechanical Forces ◽  
Lymphatic Endothelium ◽  
Canonical Pathways ◽  
Health And Disease ◽  
Multiple Cell ◽  
Sense And Respond

Mechanical forces play an important role in regulating tissue development and homeostasis in multiple cell types including bone, joint, epithelial and vascular cells, and are also implicated in the development of diseases, e.g. osteoporosis, cardiovascular disease and osteoarthritis. Defining the mechanisms by which cells sense and respond to mechanical forces therefore has important implications for our understanding of tissue function in health and disease and may lead to the identification of targets for therapeutic intervention. Mechanoactivation of the Wnt signalling pathway was first identified in osteoblasts with a key role for β-catenin demonstrated in loading-induced osteogenesis. Since then, mechanoregulation of the Wnt pathway has also been observed in stem cells, epithelium, chondrocytes and vascular and lymphatic endothelium. Wnt can signal through both canonical and non-canonical pathways, and evidence suggests that both can mediate responses to mechanical strain, stretch and shear stress. This review will discuss our current understanding of the activation of the Wnt pathway in response to mechanical forces.

scholarly journals Cytochrome P450 eicosanoids and cerebral vascular function

2011 ◽  
Vol 13 ◽  
Author(s):  
John D. Imig ◽  
Alexis N. Simpkins ◽  
Marija Renic ◽  
David R. Harder
Keyword(s):  
Blood Flow ◽  
Cytochrome P450 ◽  
Vascular Function ◽  
Therapeutic Targets ◽  
Vascular Diseases ◽  
Cell Types ◽  
Cellular Mechanisms ◽  
Molecular Therapeutic ◽  
Molecular Therapeutic Targets ◽  
Cerebral Vascular

The eicosanoids 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs), which are generated from the metabolism of arachidonic acid by cytochrome P450 (CYP) enzymes, possess a wide array of biological actions, including the regulation of blood flow to organs. 20-HETE and EETs are generated in various cell types in the brain and cerebral blood vessels, and contribute significantly to cerebral blood flow autoregulation and the coupling of regional brain blood flow to neuronal activity (neurovascular coupling). Investigations are beginning to unravel the molecular and cellular mechanisms by which these CYP eicosanoids regulate cerebral vascular function and the changes that occur in pathological states. Intriguingly, 20-HETE and the soluble epoxide hydrolase (sEH) enzyme that regulates EET levels have been explored as molecular therapeutic targets for cerebral vascular diseases. Inhibition of 20-HETE, or increasing EET levels by inhibiting the sEH enzyme, decreases cerebral damage following stroke. The improved outcome following cerebral ischaemia is a consequence of improving cerebral vascular structure or function and protecting neurons from cell death. Thus, the CYP eicosanoids are key regulators of cerebral vascular function and novel therapeutic targets for cardiovascular diseases and neurological disorders.

scholarly journals Investigation of the specificity and mechanism of action of the ULK1/AMPK inhibitor SBI-0206965

2021 ◽  
Author(s):  
Danial Ahwazi ◽  
Katyayanee Neopane ◽  
Greg R Markby ◽  
Franziska Kopietz ◽  
Ashley J Ovens ◽  
...  
Keyword(s):  
Insulin Signalling ◽  
Resistant Mutant ◽  
Cell Types ◽  
C2c12 Myotubes ◽  
Cellular Functions ◽  
Cellular Effects ◽  
Compound C ◽  
Multiple Cell ◽  
Mutant Forms

SBI-0206965, originally identified as an inhibitor of the autophagy initiator kinase ULK1, has recently been reported as a more potent and selective AMPK inhibitor relative to the widely used, but promiscuous inhibitor Compound C/Dorsomorphin. Here, we studied the effects of SBI-0206965 on AMPK signalling and metabolic readouts in multiple cell types, including hepatocytes, skeletal muscle cells and adipocytes. We observed SBI-0206965 dose dependently attenuated AMPK-activator (991)-stimulated ACC phosphorylation and inhibition of lipogenesis in hepatocytes. SBI-0206965 (≥ 25 μM) modestly inhibited AMPK signalling in C2C12 myotubes, but also inhibited insulin signalling, insulin-mediated/AMPK-independent glucose uptake, and AICA-riboside uptake. We performed an extended screen of SBI-0206965 against a panel of 140 human protein kinases in vitro, which showed SBI-0206965 inhibits several kinases, including members of AMPK-related kinases (NUAK1, MARK3/4), equally or more potently than AMPK or ULK1. This screen, together with molecular modelling, revealed that most SBI-0206965-sensitive kinases contain a large gatekeeper residue with a preference for methionine at this position. We observed that mutation of the gatekeeper methionine to a smaller side chain amino acid (threonine) rendered AMPK and ULK1 resistant to SBI-0206965 inhibition. These results demonstrate that although SBI-0206965 has utility for delineating AMPK or ULK1 signalling and cellular functions, the compound potently inhibits several other kinases and critical cellular functions such as glucose and nucleoside uptake. Our study demonstrates a role for the gatekeeper residue as a determinant of the inhibitor sensitivity and inhibitor-resistant mutant forms could be exploited as potential controls to probe specific cellular effects of SBI-0206965.

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 TUBB4A mutations result in specific neuronal and oligodendrocytic defects that closely match clinically distinct phenotypes

2017 ◽  
Vol 26 (22) ◽  
pp. 4506-4518 ◽  
Author(s):  
Julian Curiel ◽  
Guillermo Rodríguez Bey ◽  
Asako Takanohashi ◽  
Marianna Bugiani ◽  
Xiaoqin Fu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Types ◽  
Neuronal Morphology ◽  
Microtubule Dynamics ◽  
Cellular Mechanisms ◽  
Clinical Phenotypes ◽  
Cellular Effects ◽  
Spastic Quadriplegia ◽  
Myelin Gene

Abstract Hypomyelinating leukodystrophies are heritable disorders defined by lack of development of brain myelin, but the cellular mechanisms of hypomyelination are often poorly understood. Mutations in TUBB4A, encoding the tubulin isoform tubulin beta class IVA (Tubb4a), result in the symptom complex of hypomyelination with atrophy of basal ganglia and cerebellum (H-ABC). Additionally, TUBB4A mutations are known to result in a broad phenotypic spectrum, ranging from primary dystonia (DYT4), isolated hypomyelination with spastic quadriplegia, and an infantile onset encephalopathy, suggesting multiple cell types may be involved. We present a study of the cellular effects of TUBB4A mutations responsible for H-ABC (p.Asp249Asn), DYT4 (p.Arg2Gly), a severe combined phenotype with hypomyelination and encephalopathy (p.Asn414Lys), as well as milder phenotypes causing isolated hypomyelination (p.Val255Ile and p.Arg282Pro). We used a combination of histopathological, biochemical and cellular approaches to determine how these different mutations may have variable cellular effects in neurons and/or oligodendrocytes. Our results demonstrate that specific mutations lead to either purely neuronal, combined neuronal and oligodendrocytic or purely oligodendrocytic defects that closely match their respective clinical phenotypes. Thus, the DYT4 mutation that leads to phenotypes attributable to neuronal dysfunction results in altered neuronal morphology, but with unchanged tubulin quantity and polymerization, with normal oligodendrocyte morphology and myelin gene expression. Conversely, mutations associated with isolated hypomyelination (p.Val255Ile and p.Arg282Pro) and the severe combined phenotype (p.Asn414Lys) resulted in normal neuronal morphology but were associated with altered oligodendrocyte morphology, myelin gene expression, and microtubule dysfunction. The H-ABC mutation (p.Asp249Asn) that exhibits a combined neuronal and myelin phenotype had overlapping cellular defects involving both neuronal and oligodendrocyte cell types in vitro. Only mutations causing hypomyelination phenotypes showed altered microtubule dynamics and acted through a dominant toxic gain of function mechanism. The DYT4 mutation had no impact on microtubule dynamics suggesting a distinct mechanism of action. In summary, the different clinical phenotypes associated with TUBB4A reflect the selective and specific cellular effects of the causative mutations. Cellular specificity of disease pathogenesis is relevant to developing targeted treatments for this disabling condition.

scholarly journals Stromal Cells Promote Matrix Deposition, Remodelling and an Immunosuppressive Tumour Microenvironment in a 3D Model of Colon Cancer

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5998
Author(s):  
Niamh A. Leonard ◽  
Eileen Reidy ◽  
Kerry Thompson ◽  
Emma McDermott ◽  
Eleonora Peerani ◽  
...  
Keyword(s):  
Stromal Cells ◽  
3D Model ◽  
Therapeutic Targets ◽  
Cell Types ◽  
Tumour Microenvironment ◽  
Research Translation ◽  
Matrix Deposition ◽  
Multiple Cell ◽  
Cell Expression ◽  
Novel Therapeutic

Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide. CRC develops in a complex tumour microenvironment (TME) with both mesenchymal stromal cells (MSCs) and immune infiltrate, shown to alter disease progression and treatment response. We hypothesised that an accessible, affordable model of CRC that combines multiple cell types will improve research translation to the clinic and enable the identification of novel therapeutic targets. A viable gelatine-methacrloyl-based hydrogel culture system that incorporates CRC cells with MSCs and a monocyte cell line was developed. Gels were analysed on day 10 by PCR, cytokine array, microscopy and flow cytometry. The addition of stromal cells increased transcription of matrix remodelling proteins FN1 and MMP9, induced release of tumour-promoting immune molecules MIF, Serpin E1, CXCL1, IL-8 and CXCL12 and altered cancer cell expression of immunotherapeutic targets EGFR, CD47 and PD-L1. Treatment with PD153035, an EGFR inhibitor, revealed altered CRC expression of PD-L1 but only in gels lacking MSCs. We established a viable 3D model of CRC that combined cancer cells, MSCs and monocytic cells that can be used to research the role the stroma plays in the TME, identify novel therapeutic targets and improve the transitional efficacy of therapies.

Mechanisms of inflammation

2018 ◽  
Author(s):  
Roland Klingenberg ◽  
Ulf Müller-Ladner
Keyword(s):  
Rheumatoid Arthritis ◽  
Cardiovascular Disease ◽  
Therapeutic Target ◽  
Immune Cell ◽  
Cell Types ◽  
Atherosclerotic Cardiovascular Disease ◽  
Major Interest ◽  
Anti Inflammatory ◽  
Artery Disease ◽  
The Many

This chapter provides a brief summary of the immune pathogenesis of atherosclerosis, highlighting shared features with inflammatory pathways in rheumatoid arthritis (RA) described in detail in Chapter 25.4. RA constitutes a prototype autoimmune disease primarily affecting the joints but also the heart and vessels associated with increased cardiovascular mortality. Recent years have produced a wealth of novel insights into the diversity of immune cell types which either propagate or dampen inflammation in atherogenesis. Expansion of this inherent anti-inflammatory component carried by regulatory T cells may constitute a new therapeutic target to harness the progression of atherosclerotic cardiovascular disease. Among the various inflammatory mediators involved in RA pathology, cytokines (tumour necrosis factor-α‎ and interleukin-6) have gained major interest as therapeutic targets with approved therapies available. In light of the many common features in the pathogenesis of RA and atherosclerosis, these biologics are currently being evaluated in cardiovascular patients. The recently published CANTOS trial showed that IL-1 inhibition reduced adverse cardiovascular events in patients with coronary artery disease demonstrating that inflammation is a genuine therapeutic target. The near future will provide more information whether inflammation is a bona fide cardiovascular risk factor based on completion of several clinical trials using anti-inflammatory approaches in patients with both cardiovascular disease and rheumatoid arthritis.

Mechanisms of inflammation

ESC CardioMed ◽  
2018 ◽  
pp. 1104-1106
Author(s):  
Roland Klingenberg ◽  
Ulf Müller-Ladner
Keyword(s):  
Rheumatoid Arthritis ◽  
Cardiovascular Disease ◽  
Therapeutic Target ◽  
Immune Cell ◽  
Cell Types ◽  
Atherosclerotic Cardiovascular Disease ◽  
Bona Fide ◽  
Anti Inflammatory ◽  
Artery Disease ◽  
The Many

This chapter provides a brief summary of the immune pathogenesis of atherosclerosis, highlighting shared features with inflammatory pathways in rheumatoid arthritis (RA) described in detail in Chapter 25.4. RA constitutes a prototype autoimmune disease primarily affecting the joints but also the heart and vessels associated with increased cardiovascular mortality. Recent years have produced a wealth of novel insights into the diversity of immune cell types which either propagate or dampen inflammation in atherogenesis. Expansion of this inherent anti-inflammatory component carried by regulatory T cells may constitute a new therapeutic target to harness the progression of atherosclerotic cardiovascular disease. Among the various inflammatory mediators involved in RA pathology, cytokines (tumour necrosis factor-α‎ and interleukin-6) have gained major interest as therapeutic targets with approved therapies available. In light of the many common features in the pathogenesis of RA and atherosclerosis, these biologics are currently being evaluated in cardiovascular patients. The recently published CANTOS trial showed that IL-1 inhibition reduced adverse cardiovascular events in patients with coronary artery disease demonstrating that inflammation is a genuine therapeutic target. The near future will provide more information whether inflammation is a bona fide cardiovascular risk factor based on completion of several clinical trials using anti-inflammatory approaches in patients with both cardiovascular disease and rheumatoid arthritis.

Sign in / Sign up

Export Citation Format

Share Document