Publications by authors named "Peter J Little"

148 Publications

YY-11, a camel milk-derived peptide, inhibits TGF-β-mediated atherogenic signaling in human vascular smooth muscle cells.

J Food Biochem 2021 Jul 27:e13882. Epub 2021 Jul 27.

School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD, Australia.

Atherosclerosis, the major underlying pathology of cardiovascular disease, commences with the binding and trapping of lipids on modified proteoglycans, with hyperelongated glycosaminoglycan chains. Transforming growth factor (TGF)-β stimulates glycosaminoglycan elongation in vascular smooth muscle cells. We have recently shown that this TGF-β signaling pathway involves reactive oxygen species (ROS). YY-11 is a dodecapeptide derived from camel milk and it has antioxidant activity. We have investigated the role of YY-11 in blocking ROS signaling and downstream atherogenic responses. YY-11 inhibited TGF-β stimulated ROS production and inhibited the expression of genes for glycosaminoglycan chain elongation as a component of an in vitro model of atherosclerosis. This study provides a biochemical mechanism for the role of camel milk as a potential nutritional product to contribute to the worldwide amelioration of cardiovascular disease. PRACTICAL APPLICATIONS: The identification of readily accessible foods with antioxidant properties would provide a convenient and cost-effective approach community wide reducing oxidative stress induced pathologies such as atherosclerosis. We demonstrate that camel milk-derived peptide is an antioxidant that can inhibit growth factor-mediated proteoglycan modification in vitro. As proteoglycan modification is being recognized as one of the earliest atherogenic responses, these data support the notion of camel milk as a suitable nutritional product to contribute to the prevention of early stage of atherosclerosis development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jfbc.13882DOI Listing
July 2021

The zinc finger transcription factor, KLF2, protects against COVID-19 associated endothelial dysfunction.

Signal Transduct Target Ther 2021 07 12;6(1):266. Epub 2021 Jul 12.

Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.

Coronavirus disease 2019 (COVID-19) is regarded as an endothelial disease (endothelialitis) with its patho-mechanism being incompletely understood. Emerging evidence has demonstrated that endothelial dysfunction precipitates COVID-19 and its accompanying multi-organ injuries. Thus, pharmacotherapies targeting endothelial dysfunction have potential to ameliorate COVID-19 and its cardiovascular complications. The objective of the present study is to evaluate whether kruppel-like factor 2 (KLF2), a master regulator of vascular homeostasis, represents a therapeutic target for COVID-19-induced endothelial dysfunction. Here, we demonstrate that the expression of KLF2 was reduced and monocyte adhesion was increased in endothelial cells treated with COVID-19 patient serum due to elevated levels of pro-adhesive molecules, ICAM1 and VCAM1. IL-1β and TNF-α, two cytokines elevated in cytokine release syndrome in COVID-19 patients, decreased KLF2 gene expression. Pharmacologic (atorvastatin and tannic acid) and genetic (adenoviral overexpression) approaches to augment KLF2 levels attenuated COVID-19-serum-induced increase in endothelial inflammation and monocyte adhesion. Next-generation RNA-sequencing data showed that atorvastatin treatment leads to a cardiovascular protective transcriptome associated with improved endothelial function (vasodilation, anti-inflammation, antioxidant status, anti-thrombosis/-coagulation, anti-fibrosis, and reduced angiogenesis). Finally, knockdown of KLF2 partially reversed the ameliorative effect of atorvastatin on COVID-19-serum-induced endothelial inflammation and monocyte adhesion. Collectively, the present study implicates loss of KLF2 as an important molecular event in the development of COVID-19-induced vascular disease and suggests that efforts to augment KLF2 levels may be therapeutically beneficial.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41392-021-00690-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273371PMC
July 2021

Endothelial Dysfunction and Cardiovascular Disease: History and Analysis of the Clinical Utility of the Relationship.

Biomedicines 2021 Jun 20;9(6). Epub 2021 Jun 20.

Department of Pharmacy, Xinhua College, Sun Yat-sen University, Tianhe District, Guangzhou 510520, China.

The endothelium is the single-cell monolayer that lines the entire vasculature. The endothelium has a barrier function to separate blood from organs and tissues but also has an increasingly appreciated role in anti-coagulation, vascular senescence, endocrine secretion, suppression of inflammation and beyond. In modern times, endothelial cells have been identified as the source of major endocrine and vaso-regulatory factors principally the dissolved lipophilic vosodilating gas, nitric oxide and the potent vascular constricting G protein receptor agonists, the peptide endothelin. The role of the endothelium can be conveniently conceptualized. Continued investigations of the mechanism of endothelial dysfunction will lead to novel therapies for cardiovascular disease. In this review, we discuss the impact of endothelial dysfunction on cardiovascular disease and assess the clinical relevance of endothelial dysfunction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biomedicines9060699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234001PMC
June 2021

Metformin, Macrophage Dysfunction and Atherosclerosis.

Front Immunol 2021 7;12:682853. Epub 2021 Jun 7.

Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China( USTC), Hefei, China.

Metformin is one of the most widely prescribed hypoglycemic drugs and has the potential to treat many diseases. More and more evidence shows that metformin can regulate the function of macrophages in atherosclerosis, including reducing the differentiation of monocytes and inhibiting the inflammation, oxidative stress, polarization, foam cell formation and apoptosis of macrophages. The mechanisms by which metformin regulates the function of macrophages include AMPK, AMPK independent targets, NF-κB, ABCG5/8, Sirt1, FOXO1/FABP4 and HMGB1. On the basis of summarizing these studies, we further discussed the future research directions of metformin: single-cell RNA sequencing, neutrophil extracellular traps (NETs), epigenetic modification, and metformin-based combination drugs. In short, macrophages play an important role in a variety of diseases, and improving macrophage dysfunction may be an important mechanism for metformin to expand its pleiotropic pharmacological profile. In addition, the combination of metformin with other drugs that improve the function of macrophages (such as SGLT2 inhibitors, statins and IL-1β inhibitors/monoclonal antibodies) may further enhance the pleiotropic therapeutic potential of metformin in conditions such as atherosclerosis, obesity, cancer, dementia and aging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2021.682853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215340PMC
June 2021

GLP-1 receptor agonists (GLP-1RAs): cardiovascular actions and therapeutic potential.

Int J Biol Sci 2021 11;17(8):2050-2068. Epub 2021 May 11.

Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China.

Type 2 diabetes mellitus (T2DM) is closely associated with cardiovascular diseases (CVD), including atherosclerosis, hypertension and heart failure. Some anti-diabetic medications are linked with an increased risk of weight gain or hypoglycemia which may reduce the efficacy of the intended anti-hyperglycemic effects of these therapies. The recently developed receptor agonists for glucagon-like peptide-1 (GLP-1RAs), stimulate insulin secretion and reduce glycated hemoglobin levels without having side effects such as weight gain and hypoglycemia. In addition, GLP1-RAs demonstrate numerous cardiovascular protective effects in subjects with or without diabetes. There have been several cardiovascular outcomes trials (CVOTs) involving GLP-1RAs, which have supported the overall cardiovascular benefits of these drugs. GLP1-RAs lower plasma lipid levels and lower blood pressure (BP), both of which contribute to a reduction of atherosclerosis and reduced CVD. GLP-1R is expressed in multiple cardiovascular cell types such as monocyte/macrophages, smooth muscle cells, endothelial cells, and cardiomyocytes. Recent studies have indicated that the protective properties against endothelial dysfunction, anti-inflammatory effects on macrophages and the anti-proliferative action on smooth muscle cells may contribute to atheroprotection through GLP-1R signaling. In the present review, we describe the cardiovascular effects and underlying molecular mechanisms of action of GLP-1RAs in CVOTs, animal models and cultured cells, and address how these findings have transformed our understanding of the pharmacotherapy of T2DM and the prevention of CVD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/ijbs.59965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193264PMC
May 2021

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

Pharmacol Rev 2021 07;73(3):924-967

Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China (S.X., I.I., X.Z., S.L., J.W.); Sunshine Coast Health Institute, University of the Sunshine Coast, Birtinya, Australia (P.J.L.); School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland, Australia (P.J.L., D.K.); Department of Medical Biotechnology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China (H.L.); The Research Center of Basic Integrative Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China (H.L.); Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, National and Local United Engineering Laboratory of Druggability and New Drugs Evaluation, Guangzhou, China (Z.L., P.L.); College of Life Sciences, Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China (J.H.); Department of Bioengineering, Northeastern University, Boston, Massachusetts (I.C.H., E.E.E.); Department of Chemical Engineering, Northeastern University, Boston, Massachusetts (E.E.E.); Department of Neuroscience, Albert Einstein College of Medicine, New York, New York (E.E.E.); Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio (S.J.C.); and ARC Centre for Personalised Therapeutics Technologies, Department of Biochemistry and Pharmacology, School of Biomedical Science, University of Melbourne, Parkville, Victoria, Australia (A.G.S.)

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

Download full-text PDF

Source
http://dx.doi.org/10.1124/pharmrev.120.000096DOI Listing
July 2021

Curcumin Inhibits Lysophosphatidic Acid Mediated MCP-1 Expression via Blocking ROCK Signalling.

Molecules 2021 Apr 16;26(8). Epub 2021 Apr 16.

School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, QLD 4102, Australia.

Curcumin is a natural compound that has been widely used as a food additive and medicine in Asian countries. Over several decades, diverse biological effects of curcumin have been elucidated, such as anti-inflammatory and anti-oxidative activities. Monocyte chemoattractant protein-1 (MCP-1) is a key inflammatory marker during the development of atherosclerosis, and curcumin blocks MCP-1 expression stimulated by various ligands. Hence, we studied the action of curcumin on lysophosphatidic acid (LPA) mediated MCP-1 expression and explored the specific underlying mechanisms. In human vascular smooth muscle cells, LPA induces Rho-associated protein kinase (ROCK) dependent transforming growth factor receptor (TGFBR1) transactivation, leading to glycosaminoglycan chain elongation. We found that LPA also signals via the TGFBR1 transactivation pathway to regulate MCP-1 expression. Curcumin blocks LPA mediated TGFBR1 transactivation and subsequent MCP-1 expression by blocking the ROCK signalling. In the vasculature, ROCK signalling regulates smooth muscle cell contraction, inflammatory cell recruitment, endothelial dysfunction and vascular remodelling. Therefore, curcumin as a ROCK signalling inhibitor has the potential to prevent atherogenesis via multiple ways.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules26082320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073974PMC
April 2021

Poly(aspartic acid) in Biomedical Applications: From Polymerization, Modification, Properties, Degradation, and Biocompatibility to Applications.

ACS Biomater Sci Eng 2021 06 2;7(6):2083-2105. Epub 2021 Apr 2.

Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Queensland 4072, Australia.

Poly(aspartic acid) (PASP) is an anionic polypeptide that is a highly versatile, biocompatible, and biodegradable polymer that fulfils key requirements for use in a wide variety of biomedical applications. The derivatives of PASP can be readily tailored via the amine-reactive precursor, poly(succinimide) (PSI), which opens up a large window of opportunity for the design and development of novel biomaterials. PASP also has a strong affinity with calcium ions, resulting in complexation, which has been exploited for bone targeting and biomineralization. In addition, recent studies have further verified the biocompatibility and biodegradability of PASP-based polymers, which is attributed to their protein-like structure. In light of growing interest in PASP and its derivatives, this paper presents a comprehensive review on their synthesis, characterization, modification, biodegradation, biocompatibility, and applications in biomedical areas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsbiomaterials.1c00150DOI Listing
June 2021

Impact of sodium glucose cotransporter 2 (SGLT2) inhibitors on atherosclerosis: from pharmacology to pre-clinical and clinical therapeutics.

Theranostics 2021 4;11(9):4502-4515. Epub 2021 Mar 4.

Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are new oral drugs for the therapy of patients with type 2 diabetes mellitus (T2DM). Research in the past decade has shown that drugs of the SGLT2i class, such as empagliflozin, canagliflozin, and dapagliflozin, have pleiotropic effects in preventing cardiovascular diseases beyond their favorable impact on hyperglycemia. Of clinical relevance, recent landmark cardiovascular outcome trials have demonstrated that SGLT2i reduce major adverse cardiovascular events, hospitalization for heart failure, and cardiovascular death in T2DM patients with/without cardiovascular diseases (including atherosclerotic cardiovascular diseases and various types of heart failure). The major pharmacological action of SGLT2i is through inhibiting glucose re-absorption in the kidney and thus promoting glucose excretion. Studies in experimental models of atherosclerosis have shown that SGLT2i ameliorate the progression of atherosclerosis by mechanisms including inhibition of vascular inflammation, reduction in oxidative stress, reversing endothelial dysfunction, reducing foam cell formation and preventing platelet activation. Here, we summarize the anti-atherosclerotic actions and mechanisms of action of SGLT2i, with an aim to emphasize the clinical utility of this class of agents in preventing the insidious cardiovascular complications accompanying diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/thno.54498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977463PMC
July 2021

Vernolide-A and Vernodaline: Sesquiterpene Lactones with Cytotoxicity against Cancer.

J Environ Pathol Toxicol Oncol 2020 ;39(4):299-308

Faculty of Pharmacy, Ton Duc Thang University, Ho Chi Minh City, Vietnam.

Vernolide-A and vernodaline are sesquiterpene lactones isolated from genera of Vernonia. Vernolide-A and vernodaline have shown promising therapeutic properties, including antibacterial, antihelminth, and antioxidant activities. Recently, the anticancer properties of these sesquiterpene lactones have been investigated with the elucidation of effects on cell proliferation, metastasis, angiogenesis, and apoptosis. The antiproliferation and antimetastatic activities arise from targeting extracellular signal-regulated kinase 1 (ERK-1), extracellular signal-regulated kinase 2 (ERK-2), nuclear factor-κB (NF-κB), signal transducer and activator of transcription 3 (STAT3), matrix metalloproteinase 2 (MMP-2), and matrix metalloproteinase 9 (MMP9). The induction of apoptosis is due to the enhancement of caspase 9, caspase 3, while inhibition of Bcl-2 and Bcl-xL results in the release of cytochrome c into the cytosol. The activity of vernolide-A and vernodaline is hypothesized to be due to thiol reactivity through the α-methylene-γ-lactone group of sesquiterpene lactones. This review will give a brief summary of the anticancer activity of vernolide-A and vernodaline and provide information on the underlying molecular mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1615/JEnvironPatholToxicolOncol.2020034066DOI Listing
January 2021

Targeted Molecular Imaging of Cardiovascular Diseases by Iron Oxide Nanoparticles.

Arterioscler Thromb Vasc Biol 2021 02 24;41(2):601-613. Epub 2020 Dec 24.

Australian Institute for Bioengineering and Nanotechnology (K.X.V.-P., Z.P.X., H.T.T.), the University of Queensland, Australia.

Cardiovascular disease is one of the major contributors to global disease burden. Atherosclerosis is an inflammatory process that involves the accumulation of lipids and fibrous elements in the large arteries, forming an atherosclerotic plaque. Rupture of unstable plaques leads to thrombosis that triggers life-threatening complications such as myocardial infarction. Current diagnostic methods are invasive as they require insertion of a catheter into the coronary artery. Molecular imaging techniques, such as magnetic resonance imaging, have been developed to image atherosclerotic plaques and thrombosis due to its high spatial resolution and safety. The sensitivity of magnetic resonance imaging can be improved with contrast agents, such as iron oxide nanoparticles. This review presents the most recent advances in atherosclerosis, thrombosis, and myocardial infarction molecular imaging using iron oxide-based nanoparticles. While some studies have shown their effectiveness, many are yet to undertake comprehensive testing of biocompatibility. There are still potential hazards to address and complications to diagnosis, therefore strategies for overcoming these challenges are required.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/ATVBAHA.120.315404DOI Listing
February 2021

Emodin in atherosclerosis prevention: Pharmacological actions and therapeutic potential.

Eur J Pharmacol 2021 Jan 1;890:173617. Epub 2020 Oct 1.

Department of Pharmacy, Huadu District People's Hospital, Southern Medical University, Guangzhou, China. Electronic address:

Atherosclerotic plaque formation, destabilization and eventual rupture leads to the acute cardiovascular events including myocardial infarction and stroke. Emodin (PubChem CID#3220), (1,3,8-trihydroxy-6-methylanthracene-9,10-dione) is a pharmacologically bioactive constituent isolated from the traditional Chinese medicinal herb Radix rhizoma Rhei. This molecule has anti-oxidant, anti-inflammatory, anti-proliferative, anti-apoptotic and lipid-modulating effects. Experimental studies have demonstrated that emodin attenuates and stabilizes atherosclerotic plaques. In this mini-review, we provide a summary of the pharmacological actions of emodin in regulating vascular function and atherosclerosis, highlighting the therapeutic potential of this phytochemical in patients with cardiovascular disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2020.173617DOI Listing
January 2021

Lysophosphatidic acid receptor 5 transactivation of TGFBR1 stimulates the mRNA expression of proteoglycan synthesizing genes XYLT1 and CHST3.

Biochim Biophys Acta Mol Cell Res 2020 12 11;1867(12):118848. Epub 2020 Sep 11.

School of Pharmacy, Pharmacy Australia Centre of Excellence, the University of Queensland, Woolloongabba, Queensland 4102, Australia; Department of Pharmacy, Xinhua College of Sun Yat-sen University, Tianhe District, Guangzhou 510520, China. Electronic address:

Lysophosphatidic acid (LPA) via transactivation dependent signalling pathways contributes to a plethora of physiological and pathophysiological responses. In the vasculature, hyperelongation of glycosaminoglycan (GAG) chains on proteoglycans leads to lipid retention in the intima resulting in the early pathogenesis of atherosclerosis. Therefore, we investigated and defined the contribution of transactivation dependent signalling in LPA mediated GAG chain hyperelongation in human vascular smooth muscle cells (VSMCs). LPA acting via the LPA receptor 5 (LPAR5) transactivates the TGFBR1 to stimulate the mRNA expression of GAG initiation and elongation genes xylosyltransferase-1 (XYLT1) and chondroitin 6-sulfotransferase-1 (CHST3), respectively. We found that LPA stimulates ROS and Akt signalling in VSMCs, however they are not associated in LPAR5 transactivation of the TGFBR1. We observed that LPA via ROCK dependent pathways transactivates the TGFBR1 to stimulate genes associated with GAG chain elongation. We demonstrate that GPCR transactivation of the TGFBR1 occurs via a universal biochemical mechanism and the identified effectors represent potential therapeutic targets to inhibit pathophysiological effects of GPCR transactivation of the TGFBR1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbamcr.2020.118848DOI Listing
December 2020

Naringenin and naringin in cardiovascular disease prevention: A preclinical review.

Eur J Pharmacol 2020 Nov 8;887:173535. Epub 2020 Sep 8.

Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, 6734667149, Iran; Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, 6734667149, Iran. Electronic address:

Cardiovascular disease is an important cause for morbidity and mortality worldwide. Flavonoids, such as naringin, and naringenin are important natural phytochemicals in the treatment or prevention of various disorders such as obesity, cardiac diseases, diabetes, and metabolic syndrome. Naringin and naringenin have significant therapeutic potential in several diseases through anti-oxidative, anti-inflammatory, and anti-apoptotic actions; these flavonoids play a protective role in human pathophysiology. In this review, based on the latest evidence, we present a summary of the impact of naringin, and naringenin on cardiovascular disease, and analyze and discuss the basic roles of naringin and naringenin and their mechanisms of actions in cardiovascular disease and other vascular dysfunction. The data collected in this review may serve as a comprehensive reference for the effects of naringin, and naringenin in cardiovascular disease, which may be beneficial for further research and for the design of naringin and naringenin analogs as new therapeutic options for cardiovascular diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2020.173535DOI Listing
November 2020

Artemisinin inhibits glycosaminoglycan chain synthesizing gene expression but not proliferation of human vascular smooth muscle cells.

Biochem Biophys Res Commun 2020 11 28;532(2):239-243. Epub 2020 Aug 28.

School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland, 4102, Australia; Department of Pharmacy, Xinhua College of Sun Yat-sen University, Tianhe District, Guangzhou, 510520, China. Electronic address:

Pleotropic growth factor, transforming growth factor (TGF)-β drives the modification and elongation of glycosaminoglycan (GAG) chains on proteoglycans. Hyperelongated GAG chains bind and trap lipoproteins in the intima leading to the formation of atherosclerotic plaques. We have identified that phosphorylation of Smad2 linker region drives GAG chain modification. The identification of an inhibitor of Smad2 linker region phosphorylation and GAG chain modification signifies a potential therapeutic for cardiovascular diseases. Artemisinin renowned for its potent anti-malarial effects possesses a broad range of biological effects. Our aim was to characterise the anti-atherogenic role of artemisinin in vascular smooth muscle cells (VSMCs). We demonstrate that TGF-β mediated Smad2 linker region phosphorylation and GAG chain elongation was attenuated by artemisinin; however, we observed no effect on VSMC proliferation. Our data demonstrates the potential for artemisinin to be developed as a therapy to inhibit the development of atherosclerosis by prevention of lipid deposition in the vessel wall without affecting the proliferation of VSMCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2020.08.013DOI Listing
November 2020

Glutamate Attenuates the Survival Property of IGFR through NR2B Containing N-Methyl-D-aspartate Receptors in Cortical Neurons.

Oxid Med Cell Longev 2020 11;2020:5173184. Epub 2020 Aug 11.

Faculty of Health Sciences, University of Macau, Taipa, Macau, China.

Glutamate-induced neurotoxicity is involved in various neuronal diseases, such as Alzheimer's disease. We have previously reported that glutamate attenuated the survival signaling of insulin-like growth factor-1 (IGF-1) by N-methyl-D-aspartate receptors (NMDARs) in cultured cortical neurons, which is viewed as a novel mechanism of glutamate-induced neurotoxicity. However, the phosphorylation sites of IGF-1 receptor (IGF-1R) affected by glutamate remain to be elucidated, and importantly, which subtype of NMDARs plays a major role in attenuating the prosurvival effect of IGF-1 is still unknown. In the present study, glutamate was found to attenuate the tyrosine phosphorylation of the IGF-1R and the prosurvival effect of IGF-1 in primary cultured cortical neurons. NMDAR inhibitors, MK801 and AP-5, blocked the inhibitory effect of glutamate on the phosphorylation of IGF-1R and increased cell survival, while DNQX, LY341495, and CPCCOEt had no effect. Interestingly, we found that glutamate decreased the phosphorylation of tyrosine residues 1131, 1135/1136, 1250/1251, and 1316, while it had no effect on tyrosine 950 in cortical neurons. Moreover, using specific antagonists and siRNA to downregulate individual NMDAR subunits, we found that the activation of NR2B-containing NMDARs was essential for glutamate to inhibit IGF-1 signaling. These findings indicate that the glutamate-induced attenuation of IGF-1 signaling is mediated by NR2B-containing NMDARs. Our study also proposes a novel mechanism of altering neurotrophic factor signaling by the activation of NMDARs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2020/5173184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441446PMC
May 2021

Toll-like Receptor 4 Stimulates Gene Expression via Smad2 Linker Region Phosphorylation in Vascular Smooth Muscle Cells.

ACS Pharmacol Transl Sci 2020 Jun 11;3(3):524-534. Epub 2020 Mar 11.

School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland 4102, Australia.

Atherosclerosis begins in the vessel wall with the retention of low density lipoproteins to modified proteoglycans with hyperelongated glycosaminoglycan (GAG) chains. Bacterial infections produce endotoxins such as lipopolysaccharide that exacerbate the outcome of atherosclerosis by generating a heightened state of inflammation. Lipopolysaccharide (LPS) via its toll-like receptor (TLR) is well-known for its role in mediating an inflammatory response in the body. Emerging evidence demonstrates that TLRs are involved in regulating vascular functions. In this study we sought to investigate the role of LPS in proteoglycan modification and GAG chain elongation, and we hypothesize that LPS will signal via Smad2 dependent pathways to regulate GAG chain elongation. The model used human aortic vascular smooth muscle cells. GAG gene expression was assessed by quantitative real-time polymerase chain reaction. Western blotting was performed using whole-cell protein lysates to assess the signaling pathway. LPS via TLR4 stimulates the expression of GAG synthesizing enzymes to an equal extent to traditional cardiovascular agonists. LPS phosphorylates the Smad2 linker region via TAK-1/MAPK dependent pathways which correlated with genes associated with GAG chain initiation and elongation. The well-characterized role of LPS in inflammation and our data on GAG gene expression demonstrates that GAG chain elongation is the earliest marker of the inflammatory cascade in atherosclerosis development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsptsci.9b00113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296535PMC
June 2020

The Role of Toll-like Receptors in Atherothrombotic Cardiovascular Disease.

ACS Pharmacol Transl Sci 2020 Jun 6;3(3):457-471. Epub 2020 Feb 6.

School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, Queensland 4102, Australia.

Toll-like receptors (TLRs) are dominant components of the innate immune system. Activated by both pathogen-associated molecular patterns and damage-associated molecular patterns, TLRs underpin the pathology of numerous inflammation related diseases that include not only immune diseases, but also cardiovascular disease (CVD), diabetes, obesity, and cancers. Growing evidence has demonstrated that TLRs are involved in multiple cardiovascular pathophysiologies, such as atherosclerosis and hypertension. Specifically, a trial called the Canakinumab Anti-inflammatory Thrombosis Outcomes Study showed the use of an antibody that neutralizes interleukin-1β, reduces the recurrence of cardiovascular events, demonstrating inflammation as a therapeutic target and also the research value of targeting the TLR system in CVD. In this review, we provide an update of the interplay between TLR signaling, inflammatory mediators, and atherothrombosis, with an aim to identify new therapeutic targets for atherothrombotic CVD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsptsci.9b00100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296543PMC
June 2020

Metformin and Vascular Diseases: A Focused Review on Smooth Muscle Cell Function.

Front Pharmacol 2020 8;11:635. Epub 2020 May 8.

The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.

Metformin has been used in diabetes for more than 60 years and has excellent safety in the therapy of human type 2 diabetes (T2D). There is growing evidence that the beneficial health effects of metformin are beyond its ability to improve glucose metabolism. Metformin not only reduces the incidence of cardiovascular diseases (CVD) in T2D patients, but also reduces the burden of atherosclerosis (AS) in pre-diabetes patients. Vascular smooth muscle cells (VSMCs) function is an important factor in determining the characteristics of the entire arterial vessel. Its excessive proliferation contributes to the etiology of several types of CVD, including AS, restenosis, and pulmonary hypertension. Current studies show that metformin has a beneficial effect on VSMCs function. Therefore, this review provides a timely overview of the role and molecular mechanisms by which metformin acts through VSMCs to protect CVD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2020.00635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227439PMC
May 2020

Smad2 linker region phosphorylation is an autonomous cell signalling pathway: Implications for multiple disease pathologies.

Biomed Pharmacother 2020 Apr 22;124:109854. Epub 2020 Jan 22.

Department of Pharmacy, Xinhua College of Sun Yat-sen University, Tianhe District, Guangzhou, 510520, China; School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland, 4102, Australia. Electronic address:

This review will cover the signalling pathways leading to the phosphorylation of the Smad linker region independent of Smad carboxy terminal phosphorylation. Characterising Smad linker region as a signalling pathway in its own right will encourage comprehensive signalling studies to provide solutions for successful discovery and exploitation of drug targets. The review describes Smad transcription factor signalling distinct from Transforming Growth Factor (TGF)-β signalling. Novel signalling pathways represent new drug targets where these pathways are known to be involved in fibrosis, cancer and cardiovascular disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopha.2020.109854DOI Listing
April 2020

Hydrogels Based on Poly(aspartic acid): Synthesis and Applications.

Front Chem 2019 12;7:755. Epub 2019 Nov 12.

Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, QLD, Australia.

This review presents an overview on the recent progress in the synthesis, crosslinking, interpenetrating networks, and applications of poly(aspartic acid) (PASP)-based hydrogels. PASP is a synthetic acidic polypeptide that has drawn a great deal of attention in diverse applications due particularly to its biocompatibility and biodegradability. Facile modification of its precursor, poly(succinimide) (PSI), by primary amines has opened a wide window for the design of state-of-the-art hydrogels. Apart from pH-sensitivity, PASP hydrogels can be modified with suitable species in order to respond to the other desired stimuli such as temperature and reducing/oxidizing media as well. Strategies for fabrication of nanostructured PASP-based hydrogels in the form of particle and fiber are also discussed. Different cross-linking agents for PSI/PASP such as diamines, dopamine, cysteamine, and aminosilanes are also introduced. Finally, applications of PASP-based hydrogels in diverse areas particularly in biomedical are reviewed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fchem.2019.00755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861526PMC
November 2019

ROS directly activates transforming growth factor β type 1 receptor signalling in human vascular smooth muscle cells.

Biochim Biophys Acta Gen Subj 2020 01 30;1864(1):129463. Epub 2019 Oct 30.

School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD, Australia; Xinhua College of Sun Yat-sen University, Tianhe District, Guangzhou, China. Electronic address:

Background: Widely used NAPDH oxidase (Nox) inhibitor, apocynin is a prodrug that needs to be converted to its pharmacologically active form by myeloperoxidase. In myeloperoxidase deficient non phagocytic cells such as vascular smooth muscle cells (VSMCs) apocynin stimulates the production of ROS. ROS is generated by the activation of many signalling pathways, thus we have used apocynin as a pharmacological tool to characterise the role of endogenous ROS in activating the transforming growth factor beta receptor (TGFBR1) without the activation of other pathways.

Methods: The in vitro study utilized human VSMCs. Western blotting and quantitative real time PCR were performed to assess signalling pathways and gene expression, respectively. Intracellular ROS levels was measured using fluorescence detection assay.

Results: Treatment with apocynin of human VSMCs stimulated ROS production and the phosphorylation of TGFBR1 and subsequent activation of TGFBR1 signalling leading to the formation of phosphorylated Smad2 which consequently upregulates the mRNA expression of glycosaminoglycan synthesizing enzyme.

Conclusions: These findings outline a specific involvement of ROS production in TGFBR1 activation. Furthermore, because apocynin stimulates Nox and ROS production, apocynin must be used with considerable care in vitro as its actions clearly extend beyond the stimulation of Nox enzymes and it has consequences for cellular signalling.

General Significance: Apocynin can stimulate Nox leading to the production of ROS and the outcome is completely dependent upon the redox properties of the cell.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbagen.2019.129463DOI Listing
January 2020

Lysophosphatidic acid and its receptors: pharmacology and therapeutic potential in atherosclerosis and vascular disease.

Pharmacol Ther 2019 12 28;204:107404. Epub 2019 Aug 28.

School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD 4102, Australia; Department of Pharmacy, Xinhua College of Sun Yat-sen University, Tianhe District, Guangzhou 510520, China. Electronic address:

Lysophosphatidic acid (LPA) is a collective name for a set of bioactive lipid species. Via six widely distributed G protein-coupled receptors (GPCRs), LPA elicits a plethora of biological responses, contributing to inflammation, thrombosis and atherosclerosis. There have recently been considerable advances in GPCR signaling especially recognition of the extended role for GPCR transactivation of tyrosine and serine/threonine kinase growth factor receptors. This review covers LPA signaling pathways in the light of new information. The use of transgenic and gene knockout animals, gene manipulated cells, pharmacological LPA receptor agonists and antagonists have provided many insights into the biological significance of LPA and individual LPA receptors in the progression of atherosclerosis and vascular diseases. This review provides a comprehensive presentation of LPA with the highlight of the distinct role of its receptors in cell and animal models that relate to atherosclerosis and vascular diseases, and therefore provides new opportunities to reduce the burden of cardiovascular diseases. The recent drug development strategies that target LPA signaling pathways are also included in this review.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pharmthera.2019.107404DOI Listing
December 2019

Smad linker region phosphorylation is a signalling pathway in its own right and not only a modulator of canonical TGF-β signalling.

Cell Mol Life Sci 2020 Jan 12;77(2):243-251. Epub 2019 Aug 12.

Pharmacy Australia Centre of Excellence, School of Pharmacy, The University of Queensland, 20 Cornwall Street, Woolloongabba, QLD, 4102, Australia.

Transforming growth factor (TGF)-β signalling pathways are intensively investigated because of their diverse association with physiological and pathophysiological states. Smad transcription factors are the key mediators of TGF-β signalling. Smads can be directly phosphorylated in the carboxy terminal by the TGF-β receptor or in the linker region via multiple intermediate serine/threonine kinases. Growth factors in addition to hormones and TGF-β can activate many of the same kinases which can phosphorylate the Smad linker region. Historically, Smad linker region phosphorylation was shown to prevent nuclear translocation of Smads and inhibit TGF-β signalling pathways; however, it was subsequently shown that Smad linker region phosphorylation can be a driver of gene expression. This review will cover the signalling pathways of Smad linker region phosphorylation that drive the expression of genes involved in pathology and pathophysiology. The role of Smad signalling in cell biology is expanding rapidly beyond its role in TGF-β signalling and many signalling paradigms need to be re-evaluated in terms of Smad involvement.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00018-019-03266-3DOI Listing
January 2020

GPCR transactivation signalling in vascular smooth muscle cells: role of NADPH oxidases and reactive oxygen species.

Vasc Biol 2019 23;1(1):R1-R11. Epub 2019 Jul 23.

School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland, Australia.

The discovery and extension of G-protein-coupled receptor (GPCR) transactivation-dependent signalling has enormously broadened the GPCR signalling paradigm. GPCRs can transactivate protein tyrosine kinase receptors (PTKRs) and serine/threonine kinase receptors (S/TKRs), notably the epidermal growth factor receptor (EGFR) and transforming growth factor-β type 1 receptor (TGFBR1), respectively. Initial comprehensive mechanistic studies suggest that these two transactivation pathways are distinct. Currently, there is a focus on GPCR inhibitors as drug targets, and they have proven to be efficacious in vascular diseases. With the broadening of GPCR transactivation signalling, it is therefore important from a therapeutic perspective to find a common transactivation pathway of EGFR and TGFBR1 that can be targeted to inhibit complex pathologies activated by the combined action of these receptors. Reactive oxygen species (ROS) are highly reactive molecules and they act as second messengers, thus modulating cellular signal transduction pathways. ROS are involved in different mechanisms of GPCR transactivation of EGFR. However, the role of ROS in GPCR transactivation of TGFBR1 has not yet been studied. In this review, we will discuss the involvement of ROS in GPCR transactivation-dependent signalling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/VB-18-0004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439842PMC
July 2019

Mechanisms of PAR-1 mediated kinase receptor transactivation: Smad linker region phosphorylation.

J Cell Commun Signal 2019 Dec 9;13(4):539-548. Epub 2019 Jul 9.

School of Pharmacy, University of Queensland, The University of Queensland, 20 Cornwall Street, Woolloongabba, QLD 4102, Australia.

Protease activated receptors (PARs) transactivate both epidermal growth factor receptors (EGFR) and transforming growth factor (TGF)-β receptors (TGFBR1) in vascular smooth muscle leading to the increased expression of genes (CHST11 and CHSY1) which are rate limiting for the enzymes that mediate hyperelongation of glycosaminoglycan (GAG) chains on the lipid-binding proteoglycan, biglycan. This is an excellent model to investigate mechanisms of transactivation as the processes are biochemically distinct. EGFR transactivation is dependent on the classical matrix metalloprotease (MMP) based triple membrane bypass mechanism and TGFBR1 transactivation is dependent on Rho/ROCK signalling and integrins. We have shown that all kinase receptor signalling is targeted towards phosphorylation of the linker region of the transcription factor, Smad2. We investigated the mechanisms of thrombin mediated kinase receptor transactivation signalling using anti-phospho antibodies and Western blotting and gene expression by RT-PCR. Thrombin stimulation of phospho-Smad2 (Ser 245/250/255) and of phospho-Smad2(Thr220) via EGFR transactivation commences quickly and extends out to at least 4 h whereas transactivation via TGFBR1 is delayed for 120 min but also persists for at least 4 h. Signalling of thrombin stimulated Smad linker region phosphorylation is approximately equally inhibited by the MMP inhibitor, GM6001 and the ROCK inhibitor, Y27632, and similarly expression of CHST11 and CHSY1 is approximately equally inhibited by GM6001 and Y27632. The data establishes Smad linker region phosphorylation as a central target of all transactivation signalling of GAG gene expression and thus an upstream kinase may be a target to prevent all transactivation signalling and its pathophysiological consequences.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12079-019-00527-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946789PMC
December 2019

Treatment of atherosclerotic plaque: perspectives on theranostics.

J Pharm Pharmacol 2019 Jul 25;71(7):1029-1043. Epub 2019 Apr 25.

Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Qld, Australia.

Objectives: Atherosclerosis, a progressive condition characterised by the build-up of plaque due to the accumulation of low-density lipoprotein and fibrous substances in the damaged arteries, is the major underlying pathology of most cardiovascular diseases. Despite the evidence of the efficacy of the present treatments for atherosclerosis, the complex and poorly understood underlying mechanisms of atherosclerosis development and progression have prevented them from reaching their full potential. Novel alternative treatments like usage of nanomedicines and theranostics are gaining attention of the researchers worldwide. This review will briefly discuss the current medications for the disease and explore potential future developments based on theranostics nanomaterials that may help resolve atherosclerotic cardiovascular disease.

Key Findings: Various drugs can slow the effects of atherosclerosis. They include hyperlipidaemia medications, anti-platelet drugs, hypertension and hyperglycaemia medications. Most of the theranostic agents developed for atherosclerosis have shown the feasibility of rapid and noninvasive diagnosis, as well as effective and specific treatment in animal models. However, there are still some limitation exist in their structure design, stability, targeting efficacy, toxicity and production, which should be optimized in order to develop clinically acceptable nanoparticle based theronostics for atherosclerosis.

Summary: Current medications for atherosclerosis and potential theranostic nanomaterials developed for the disease are discussed in the current review. Further investigations remain to be carried out to achieve clinical translation of theranostic agents for atherosclerosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jphp.13092DOI Listing
July 2019

Non-invasive imaging techniques for the differentiation of acute and chronic thrombosis.

Thromb Res 2019 May 14;177:161-171. Epub 2019 Mar 14.

School of Pharmacy, Pharmacy Australia Centre of Excellence, University of Queensland, Woolloongabba, Queensland 4102, Australia; Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia. Electronic address:

Thrombosis is the localized clotting of blood that can occur in both the arterial and venous circulation. It is a key factor in the pathogenesis of acute coronary syndrome, myocardial infarction and stroke and the primary cause of deep vein thrombosis and pulmonary embolism. Rapid and accurate diagnosis of thrombotic episodes is crucial in reducing the morbidity and potential mortality associated with arterial and venous thrombotic disorders by allowing early targeted therapeutic interventions. From a clinical perspective the ability to accurately assess the age and composition of thrombus is highly desirable given that anticoagulation and, in particular, fibrinolytic therapies are more effective in treating acute rather than chronic thrombosis. While there are no imaging tests used in routine clinical practice that can reliably determine the age of thrombus and differentiate between acute and chronic thrombosis there are several emerging non-invasive techniques that can provide an indication of the age of a thrombus depending on its location in the body. Examples of techniques developed for venous thrombosis include Doppler imaging with venous duplex ultrasonography, ultrasound B-mode imaging integrated with IER (intrinsic mode functions-based echogenicity ratio), elastography, scintigraphy imaging with Tc-recombinant tissue plasminogen activator (Tc-rt-PA), and magnetic resonance direct thrombus imaging (MDRTI). Magnetic resonance imaging (MRI) has been used to noninvasively detect and differentiate acute and chronic arterial and venous thrombosis. These methods have limitations that need further investigation to enable cost-effective and clinically relevant treatment practices to be established in the future. This review will discuss the difference between acute and chronic thrombosis and the role of non-invasive imaging techniques in discriminating between the two.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.thromres.2019.03.009DOI Listing
May 2019

Targeting Mechanosensitive Transcription Factors in Atherosclerosis.

Trends Pharmacol Sci 2019 04 28;40(4):253-266. Epub 2019 Feb 28.

Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. Electronic address:

Atherosclerosis is the primary underlying cause of cardiovascular disease which preferentially develops at arterial regions exposed to disturbed flow (DF), but much less at regions of unidirectional laminar flow (UF). Recent studies have demonstrated that DF and UF differentially regulate important aspects of endothelial function, such as vascular inflammation, oxidative stress, vascular tone, cell proliferation, senescence, mitochondrial function, and glucose metabolism. DF and UF regulate vascular pathophysiology via differential regulation of mechanosensitive transcription factors (MSTFs) (KLF2, KLF4, NRF2, YAP/TAZ/TEAD, HIF-1α, NF-κB, AP-1, and others). Emerging studies show that MSTFs represent promising therapeutic targets for the prevention and treatment of atherosclerosis. We present here a comprehensive overview of the role of MSTFs in atherosclerosis, and highlight future directions for developing novel therapeutic agents by targeting MSTFs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tips.2019.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433497PMC
April 2019

Endothelin-1 increases CHSY-1 expression in aortic endothelial cells via transactivation of transforming growth factor β type I receptor induced by type B receptor endothelin-1.

J Pharm Pharmacol 2019 Jun 27;71(6):988-995. Epub 2019 Feb 27.

Hyperlipidemia Research Center, Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

Objectives: TGF-β through hyperelongation of glycosaminoglycan (GAG) chains leads to binding of low-density lipoproteins to the proteoglycans. The vasoactive peptide, endothelin-1 (ET-1), plays a key role in the development of atherosclerosis. This study addressed the question whether ET-1 by activating the Rho kinase and cytoskeletal rearrangement can transactivate the TGF-β receptor leading to phosphorylation of the transcription factor Smad2 and increased expression of the GAG chain synthesizing enzyme such as chondroitin synthase-1 (CHSY-1) in bovine aortic endothelial cells (BAECs).

Methods: In this study, intermediates in ET-1-induced Smad2C phosphorylation and the protein level of CHSY-1 were identified and quantified by Western blotting.

Key Findings: Endothelin-1 caused time-dependent phosphorylation of Smad2C which was inhibited in the presence of the endothelin B receptor antagonist, BQ788. The response to ET-1 was inhibited by the Rho/ROCK kinase antagonist, Y27632 and by cytochalasin D, an inhibitor of actin polymerization but the ET-1-mediated pSmad2C was not inhibited by the matrix metalloproteinase (MMP) inhibitor, GM6001. ET-1 increased CHSY-1 protein level, which was inhibited in the presence of BQ788, cytochalasin D and Y27632.

Conclusions: Endothelin-1 signalling via the ET receptor utilizes cytoskeletal rearrangement and Rho kinase but not MMPs leading to TβRI transactivation signalling and phosphorylation of Smad2C and through this pathway increased the level of CHSY-1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jphp.13081DOI Listing
June 2019
-->