scholarly journals Acetylsalicylic Acid Reduces Passive Aortic Wall Stiffness and Cardiovascular Remodelling in a Mouse Model of Advanced Atherosclerosis

2021 ◽  
Vol 23 (1) ◽  
pp. 404
Author(s):  
Lynn Roth ◽  
Miche Rombouts ◽  
Dorien M. Schrijvers ◽  
Besa Emini Veseli ◽  
Wim Martinet ◽  
...  
Keyword(s):  
Drinking Water ◽  
Acetylsalicylic Acid ◽  
Cardiac Fibrosis ◽  
Elastic Fibre ◽  
Neutrophil Lymphocyte Ratio ◽  
Therapeutic Benefits ◽  
Wall Stiffness ◽  
Antithrombotic Effects ◽  
Fibrillin 1 ◽  
Cv Disease

Acetylsalicylic acid (ASA) is widely used in secondary prevention of cardiovascular (CV) disease, mainly because of its antithrombotic effects. Here, we investigated whether ASA can prevent the progression of vessel wall remodelling, atherosclerosis, and CV complications in apolipoprotein E deficient (ApoE−/−) mice, a model of stable atherosclerosis, and in ApoE−/− mice with a mutation in the fibrillin-1 gene (Fbn1C1039G+/−), which is a model of elastic fibre fragmentation, accompanied by exacerbated unstable atherosclerosis. Female ApoE−/− and ApoE−/−Fbn1C1039G+/− mice were fed a Western diet (WD). At 10 weeks of WD, the mice were randomly divided into four groups, receiving either ASA 5 mg/kg/day in the drinking water (ApoE−/− (n = 14), ApoE−/−Fbn1C1039G+/− (n = 19)) or plain drinking water (ApoE−/− (n = 15), ApoE−/−Fbn1C1039G+/− (n = 21)) for 15 weeks. ApoE−/−Fbn1C1039G+/− mice showed an increased neutrophil–lymphocyte ratio (NLR) compared to ApoE−/− mice, and this effect was normalised by ASA. In the proximal ascending aorta wall, ASA-treated ApoE−/−Fbn1C1039G+/− mice showed less p-SMAD2/3 positive nuclei, a lower collagen percentage and an increased elastin/collagen ratio, consistent with the values measured in ApoE−/− mice. ASA did not affect plaque progression, incidence of myocardial infarction and survival of ApoE−/−Fbn1C1039G+/− mice, but systolic blood pressure, cardiac fibrosis and hypertrophy were reduced. In conclusion, ASA normalises the NLR, passive wall stiffness and cardiac remodelling in ApoE−/−Fbn1C1039G+/− mice to levels observed in ApoE−/− mice, indicating additional therapeutic benefits of ASA beyond its classical use.

Abstract 316: A Potential Mechanism Involving mTOR For The Expression Of CTGF In Agonist-stimulated Adult Cardiomyocytes

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Kamala P Sundararaj ◽  
Sundaravadivel Balasubramanian ◽  
Dorea Pleasant ◽  
Dhandapani Kuppuswamy
Keyword(s):  
Mrna Expression ◽  
Wound Repair ◽  
Cardiac Fibrosis ◽  
Interstitial Fibrosis ◽  
Treatment Options ◽  
Tissue Growth ◽  
Dependent Manner ◽  
Potential Mechanism ◽  
Wall Stiffness ◽  
Wide Range

Cardiac hypertrophy ensues as a response to multiple stimuli, such as mechanical stress, neurohumoral activation, growth factors and cytokines. Connective Tissue Growth Factor (CTGF), a potent fibrogenic cytokine, regulates a wide range of biological functions including ECM deposition, wound repair, angiogenesis, migration, differentiation, survival and proliferation. While CTGF overexpression in fibroblasts has been shown to be responsible for fibrosis in various organs, controversy exists about the source of CTGF. Since interstitial fibrosis contributes to ventricular wall stiffness and impairs diastolic function, understating how key factors such as CTGF are expressed and released for the genesis of fibrosis in the hypertrophying heart is important to develop new treatment options. To this end, we explored the signaling pathway(s) involved in the phenylephrine (PE), a hypertrophic agonist, induced expression of CTGF by cardiomyocytes (CMs). Since mammalian target of rapamycin (mTOR) is reported to regulate PE-induced hypertrophic signaling, we hypothesize that mTOR plays a role in PE induced CTGF expression in CMs. To test if CMs produce CTGF, we treated adult feline CMs with phenylephrine. PE stimulated CTGF mRNA expression in a dose and time dependent manner. mTOR forms two distinct complexes, mTORC1 and mTORC2. Whereas both complexes are sensitive to a pharmacological inhibitor Torin1, only mTORC1 is sensitive to Rapamycin inhibition. Our results indicate that PE stimulated CTGF expression could be substantially enhanced by torin1 pretreatment of CMs. Moreover, shRNA mediated silencing of Rictor in CMs, one of the components of mTORC2, significantly augmented the PE induced CTGF mRNA expression. But mTORC1 inhibition using Rapamycin or activation of its downstream target S6K1 using Rapamycin resistant S6K1 adenovirus had no impact in PE -stimulated CTGF expression. The same trend was also observed in the level of secreted CTGF. In conclusion, these results strongly indicate that mTORC2 plays a repressive role in CTGF mRNA expression in adult CMs, and that the loss of such repression in PO myocardium might be a potential mechanism for the onset of cardiac fibrosis in hypertrophying myocardium.

scholarly journals Fibulin-5 interacts with fibrillin-1 molecules and microfibrils

2005 ◽  
Vol 388 (1) ◽  
pp. 1-5 ◽  
Author(s):  
Lyle J. FREEMAN ◽  
Amanda LOMAS ◽  
Nigel HODSON ◽  
Michael J. SHERRATT ◽  
Kieran T. MELLODY ◽  
...  
Keyword(s):  
Molecular Interactions ◽  
Elastic Fibre ◽  
Dependent Manner ◽  
Terminal Sequence ◽  
Fibre Formation ◽  
Fibrillin 1 ◽  
Dose Dependent

Fibulin-5 plays an important role in elastic fibre formation in vivo. We have investigated the molecular interactions between fibulin-5 and components of fibrillin-rich microfibrils which form a template for elastin. Fibulin-5 interacted in a dose-dependent manner with a fibrillin-1 N-terminal sequence and with tropoelastin, but not with MAGP-1 (microfibril-associated glycoprotein-1) or decorin. Fibulin-5 did not inhibit interactions between fibrillin-1 N- and C-terminal fragments, or fibrillin-1 interactions with tropoelastin. Fibulin-5 may provide a link between tropoelastin and microfibrils in the pericellular space during elastic fibre assembly.

scholarly journals A primer on current progress in cardiac fibrosis

2017 ◽  
Vol 95 (10) ◽  
pp. 1091-1099 ◽  
Author(s):  
Danah Al Hattab ◽  
Michael P. Czubryt
Keyword(s):  
Cardiovascular Disease ◽  
Cardiac Fibrosis ◽  
Significant Risk ◽  
Specific Treatment ◽  
Significant Risk Factor ◽  
Novel Treatments ◽  
Matrix Deposition ◽  
Wall Stiffness ◽  
Systolic And Diastolic Function ◽  
New Research

Cardiac fibrosis is a significant global health problem that is closely associated with multiple forms of cardiovascular disease, including myocardial infarction, dilated cardiomyopathy, and diabetes. Fibrosis increases myocardial wall stiffness due to excessive extracellular matrix deposition, causing impaired systolic and diastolic function, and facilitating arrhythmogenesis. As a result, patient morbidity and mortality are often dramatically elevated compared with those with cardiovascular disease but without overt fibrosis, demonstrating that fibrosis itself is both a pathologic response to existing disease and a significant risk factor for exacerbation of the underlying condition. The lack of any specific treatment for cardiac fibrosis in patients suffering from cardiovascular disease is a critical gap in our ability to care for these individuals. Here we provide an overview of the development of cardiac fibrosis, and discuss new research directions that have recently emerged and that may lead to the creation of novel treatments for patients with cardiovascular diseases. Such treatments would, ideally, complement existing therapy by specifically focusing on amelioration of fibrosis.

Chronic angiotensin-(1–7) prevents cardiac fibrosis in DOCA-salt model of hypertension

2006 ◽  
Vol 290 (6) ◽  
pp. H2417-H2423 ◽  
Author(s):  
Justin L. Grobe ◽  
Adam P. Mecca ◽  
Haoyu Mao ◽  
Michael J. Katovich
Keyword(s):  
Blood Pressure ◽  
Drinking Water ◽  
Cardiac Hypertrophy ◽  
Cross Sections ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Collagen Deposition ◽  
Sprague Dawley ◽  
Artery Cannulation ◽  
Blood Pressure Responses

Cardiac remodeling is a hallmark hypertension-induced pathophysiology. In the current study, the role of the angiotensin-(1–7) fragment in modulating cardiac remodeling was examined. Sprague-Dawley rats underwent uninephrectomy surgery and were implanted with a deoxycorticosterone acetate (DOCA) pellet. DOCA animals had their drinking water replaced with 0.9% saline solution. A subgroup of DOCA-salt animals was implanted with osmotic minipumps, which delivered angiotensin-(1–7) chronically (100 ng·kg−1·min−1). Control animals underwent sham surgery and were maintained on normal drinking water. Blood pressure was measured weekly with the use of the tail-cuff method, and after 4 wk of treatment, blood pressure responses to graded doses of angiotensin II were determined by direct carotid artery cannulation. Ventricle size was measured, and cross sections of the heart ventricles were paraffin embedded and stained using Masson's Trichrome to measure interstitial and perivascular collagen deposition and myocyte diameter. DOCA-salt treatment caused significant increases in blood pressure, cardiac hypertrophy, and myocardial and perivascular fibrosis. Angiotensin-(1–7) infusion prevented the collagen deposition effects without any effect on blood pressure or cardiac hypertrophy. These results indicate that angiotensin-(1–7) selectively prevents cardiac fibrosis independent of blood pressure or cardiac hypertrophy in the DOCA-salt model of hypertension.

scholarly journals Elastic fibres in health and disease

2013 ◽  
Vol 15 ◽  
Author(s):  
Andrew K. Baldwin ◽  
Andreja Simpson ◽  
Ruth Steer ◽  
Stuart A. Cain ◽  
Cay M. Kielty
Keyword(s):  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Elastic Fibre ◽  
Cutis Laxa ◽  
Elastic Recoil ◽  
Elastic Fibres ◽  
Connective Tissues ◽  
Inflammatory Damage ◽  
Fibrillin 1 ◽  
Health And Disease

Elastic fibres are insoluble components of the extracellular matrix of dynamic connective tissues such as skin, arteries, lungs and ligaments. They are laid down during development, and comprise a cross-linked elastin core within a template of fibrillin-based microfibrils. Their function is to endow tissues with the property of elastic recoil, and they also regulate the bioavailability of transforming growth factor β. Severe heritable elastic fibre diseases are caused by mutations in elastic fibre components; for example, mutations in elastin cause supravalvular aortic stenosis and autosomal dominant cutis laxa, mutations in fibrillin-1 cause Marfan syndrome and Weill–Marchesani syndrome, and mutations in fibulins-4 and -5 cause autosomal recessive cutis laxa. Acquired elastic fibre defects include dermal elastosis, whereas inflammatory damage to fibres contributes to pathologies such as pulmonary emphysema and vascular disease. This review outlines the latest understanding of the composition and assembly of elastic fibres, and describes elastic fibre diseases and current therapeutic approaches.

scholarly journals Fibrillin-1 and −2 contain heparin-binding sites important for matrix deposition and that support cell attachment

2003 ◽  
Vol 375 (2) ◽  
pp. 425-432 ◽  
Author(s):  
Timothy M. RITTY ◽  
Thomas J. BROEKELMANN ◽  
Claudio C. WERNECK ◽  
Robert P. MECHAM
Keyword(s):  
Extracellular Matrix ◽  
Cell Attachment ◽  
Heparan Sulphate ◽  
Cell Types ◽  
Binding Activity ◽  
Elastic Fibre ◽  
Heparin Binding ◽  
Matrix Deposition ◽  
Organ Systems ◽  
Fibrillin 1

Fibrillin-1 and −2 are large modular extracellular matrix glycoproteins found in many vertebrate organ systems and are known to be key components of the elastic fibre. In the present study, we identify a new heparin-binding region in fibrillin-2 between exons 18 and 24. Additionally, we have narrowed the location of heparin-binding activity previously identified in fibrillin-1 to the last 17 residues of the mature proteolytically processed protein. This domain demonstrated higher activity as a multimer than as a monomer. The fibrillin-1 C-terminal site supported cell attachment in each of nine cell types tested. Attachment was shown to be mediated by cell-surface heparan sulphate proteoglycans. Fibrillin-1 has been shown previously to have heparin-binding activity that is important for matrix deposition of the molecule by fibroblasts. This function in deposition was confirmed in two additional fibrillin-producing cell types (osteosarcoma and epithelial cells) for the deposition of both fibrillin-1 and −2 into the extracellular matrix.

scholarly journals Effects of an allostatic modulator on the behavior and blood indicators of young bulls after transport

2019 ◽  
Vol 5 (4) ◽  
Author(s):  
María Salud Rubio Lozano ◽  
Rubén Danilo Méndez Medina ◽  
Karla Reyes Mayorga ◽  
María Elena Rubio García ◽  
Tania Manu Ngapo ◽  
...  
Keyword(s):  
Ascorbic Acid ◽  
Drinking Water ◽  
Sodium Chloride ◽  
Acetylsalicylic Acid ◽  
Potassium Chloride ◽  
Creatinine Kinase ◽  
Agonistic Interactions ◽  
Transport Control ◽  
Biochemical Components ◽  
Cortisol Levels

An allostatic modulator (AM) composed of ascorbic acid, acetylsalicylic acid, sodium chloride and potassium chloride was dissolved in the drinking water of three groups of young bulls (n = 7) and administered to them for 7 d after 20.42 h of transport (Control (C) = 0 g/head/d, G2 = 30 g/head/d, G3 = 60 g/head/d). The effects of the AM on behavior and blood cellular and biochemical components were measured. G3 animals spent less time lying and more time standing than C animals (P = 0.001 and P = 0.02, respectively), indicating less fatigue. G3 bulls presented a lower frequency of agonistic interactions than those in the G2 group (P = 0.001), suggesting a possible effect on aggression that warrants further evaluation. The AM affected creatinine kinase (CK) activity in the G2 group compared to the C group (P = 0.04), suggesting an effect of AM components that has not been previously reported. Cortisol levels remained unaffected by AM supplementation (P = 0.55). These preliminary findings suggest an effect of supplementing cattle with an AM after long-haul transport.

Sign in / Sign up

Export Citation Format

Share Document