Copper-induced reduction in myocardial fibrosis is associated with increased matrix metalloproteins in a rat model of cardiac hypertrophy

Metallomics ◽  
2018 ◽  
Vol 10 (1) ◽  
pp. 201-208 ◽  
Author(s):  
Yinjie Liu ◽  
Ying Xiao ◽  
Jiaming Liu ◽  
Li Feng ◽  
Y. James Kang
Keyword(s):  
Cardiac Hypertrophy ◽  
Myocardial Fibrosis ◽  
Rat Model ◽  
Cardiac Fibrosis ◽  
Collagen Deposition ◽  
Matrix Metalloproteins

AAC induces Cu loss from the heart and depressed MMP-2 in combination with increased TIMPs, leading to increased collagen deposition. TETA replenishes Cu in the heart, increases MMP-2, and decreases TIMP-1 and -2, collectively resulting in reduction in cardiac 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 Biomarkers in patients with myocardial fibrosis

2017 ◽  
Vol 12 (1) ◽  
pp. 337-344 ◽  
Author(s):  
Zhe An ◽  
Guang Yang ◽  
Haikuo Zheng ◽  
Wei Nie ◽  
Guohui Liu
Keyword(s):  
Heart Failure ◽  
Cardiovascular Diseases ◽  
Early Detection ◽  
Myocardial Fibrosis ◽  
Gold Standard ◽  
Cardiac Fibrosis ◽  
Collagen Deposition ◽  
Circulating Biomarkers ◽  
Galectin 3 ◽  
Noninvasive Assessment

AbstractMyocardial fibrosis is observed in many cardiovascular diseases including hypertension, heart failure and cardiomyopathy. Myocardial fibrosis has been proved to be reversible and treatable only under timely intervention, which makes early detection and assessment of fibrosis crucial. Aside from tissue biopsy as the gold standard for the diagnosis of myocardial fibrosis, circulating biomarkers have been adopted as noninvasive assessment of this lesion. Dysregulated collagen deposition is thought to be the major cause of myocardial fibrosis. Collagens, procollagens, TGF-β, TIMP, galectin-3, and microRNAs are thought to be indicators of myocardial fibrosis. In this review, we summarize the molecules that are frequently used as biomarkers in diagnosis of cardiac fibrosis. Mechanisms of fibrosis that they take part in are also introduced.

Loss of smooth muscle SDF-1/CXCL12 leads to cardiac hypertrophy and aortic valve stenosis

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S.K Ghadge ◽  
M Messner ◽  
H Seiringer ◽  
T Zeller ◽  
D Boernigen ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Aortic Valve ◽  
Aortic Stenosis ◽  
Cardiac Hypertrophy ◽  
Smooth Muscle Cells ◽  
Aortic Valve Stenosis ◽  
Cardiac Fibrosis ◽  
Muscle Cells ◽  
Funding Source ◽  
Lineage Tracking

Abstract Background Stromal cell-derived factor-1 (SDF-1 or CXCL12) and its receptors CXCR4/CXCR7 have prominent role in cardiovascular development and myocardial repair following ischemic injury. Nevertheless, detailed mechanisms of the cell specific role of SDF-1 are poorly understood. Since SDF-1-EGFP lineage tracking revealed high expression of SDF-1 in smooth muscle cells, we aimed to investigate the cell specific role by generating a smooth muscle cell specific SDF-1 (SM-SDF-1−/−) knockout mouse model. Methods SDF-1 expression was analyzed utilizing SDF-1-EGFP reporter mice. Conditional SM-SDF-1 KO mice were generated using Tagln-Cre; SDF-1fl/fl mice. Hearts were analysed with histology and high-resolution episcopic microscopy. Cardiac function was assessed utilizing echocardiography. RNAseq, qRT-PCR, flow cytometry and western blotting were performed. Cardiac fibrosis, apoptotic index, cell proliferation, aortic valve calcification were analyzed. SM-SDF-1−/− mice were treated with the CXCR7 agonist TC14012 (10mg/kg/I.P). Results SDF-1-EGFP lineage tracking and immunofluorescence revealed high expression of SDF-1 particularly in smooth muscle cells and less frequently in perivascular and endothelial cells. Conditional SM-SDF-1−/− mice showed a high pre- and perinatal mortality (50%). Immunohistochemistry of SM-SDF-1−/− mice revealed severe cardiac hypertrophy, associated with increased cardiac fibrosis, apoptotic cell death, thinned and dilated arteries and significantly decreased M2 like CD11b+/CD206+ cells. Echocardiography confirmed concentric hypertrophy, with decreased stroke volume. As a possible reason for cardiac hypertrophy, SDF-1 mutants exhibited aortic stenosis due to aortic valve thickening associated with downregulation of the SDF-1 co-receptor CXCR7. We further noticed increased plasma levels of SDF-1 in aortic stenosis patients suggesting a cardioprotective role. Transcriptome analyses from KO hearts showed an abnormal extracellular matrix (ECM) remodelling with a specific upregulation of the important valve related proteoglycans Versican, Glycan. Western blot analysis revealed activation of AKT and ERK, whereas CXCR7 expression was significantly downregulated in KO mice. To rescue the phenotype we treated KO mice with the CXCR7 agonist (TC14012) which partially attenuated aortic valve remodelling through activation of the ERK signalling pathway. Conclusion Our data suggest that SDF-1 is critically involved in maintaining the homeostasis of the aortic valve by regulating CXCR7 signalling. Pharmacological activation of CXCR7 might be a promising therapeutic target to limit the progression of aortic valve stenosis. Ghadge_SM-SDF-1−/− Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Austrian Science Fund, Austrian research promotion agency

Abstract P317: Cardiac Fibroblast GSK3α Promotes Myocardial Fibrotic Remodeling Through GSK3α-ERK-IL11 Signaling Circuit

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Prachi Umbarkar ◽  
Sultan Tousif ◽  
Anand P Singh ◽  
Joshua C Anderson ◽  
qinkun zhang ◽  
...  
Keyword(s):  
Myocardial Fibrosis ◽  
Cardiac Fibrosis ◽  
Critical Role ◽  
Flow Cytometric Analysis ◽  
Collagen Gel ◽  
Pressure Overload ◽  
Negative Regulator ◽  
Post Injury

Background: Myocardial fibrosis contributes significantly to heart failure (HF). Fibroblasts are among the predominant cell type in the heart and are primary drivers of fibrosis. To identify the kinases involved in fibrosis, we analyzed the kinome of mouse cardiac fibroblasts (CF) isolated from normal and failing hearts. This unbiased screening revealed the critical role of the GSK-3 family-centric pathways in fibrosis. Previously we have shown that among two isoforms of GSK3, CF-GSK3β acts as a negative regulator of fibrosis in the injured heart. However, the role of CF-GSK3α in the pathogenesis of cardiac diseases is completely unknown. Methods and Results: To define the role of CF-GSK3α in HF, we employed two novel fibroblast-specific KO mouse models. Specifically, GSK3α was deleted from fibroblasts or myofibroblasts with tamoxifen-inducible Tcf21- or periostin- promoter-driven Cre recombinase. In both models, GSK3α deletion restricted pressure overload-induced cardiac fibrosis and preserved cardiac function. We examined the effect of GSK3α deletion on myofibroblast transformation and pro-fibrotic TGFβ1-SMAD3 signaling in vitro . A significant reduction in cell migration, collagen gel contraction, and α-SMA expression in TGFβ1-treated KO CFs confirmed that GSK3α is required for myofibroblast transformation. Surprisingly, GSK3α deletion did not affect SMAD3 activation, indicating the pro-fibrotic role of GSK3α is SMAD3 independent. To further delineate the underlying mechanisms, proteins were isolated from CFs of WT and KO mice at 4 weeks post-injury, and kinome profiling was performed. The kinome analysis identified the downregulation of RAF family kinase activity in KO CFs. Moreover, mapping of significantly altered kinases against literature annotated interactions generated ERK-centric networks. Consistently, flow cytometric analysis of CFs confirmed significantly low levels of pERK in KO mice. Additionally, our in vitro studies demonstrated that GSK3α deletion prevents TGFβ1-induced ERK activation. Interestingly, IL-11, a pro-fibrotic downstream effector of TGFβ1, was remarkably reduced in KO CFs and ERK inhibition further decreased IL-11 expression. Taken together, herein, we discovered the GSK3α-ERK-IL-11 signaling as a critical pro-fibrotic pathway in the heart. Strategies to inhibit this pro-fibrotic network could prevent adverse fibrosis and HF. Conclusion: CF-GSK3α plays a causal role in myocardial fibrosis that could be therapeutically targeted for future clinical applications.

Abstract 13810: TT-00920, a Clinical Stage Novel Phosphodiesterase 9 Inhibitor, Protects Against Heart Failure in a Rat Model of Myocardial Infarction

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Zejuan Sheng ◽  
Xiaoyan Qiang ◽  
Guoyu Li ◽  
Huimin Wang ◽  
Wenxin Dong ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Cardiac Function ◽  
Rat Model ◽  
Cardiac Fibrosis ◽  
Clinical Stage ◽  
Left Ventricular ◽  
Guanosine Monophosphate ◽  
Therapeutic Effects ◽  
Dependent Manner

Introduction: Phosphodiesterase 9 (PDE9) controls natriuretic-peptide-stimulated cyclic guanosine monophosphate in cardiac myocytes and is stongly upregulated in human heart failure, suggesting its potential as a promising therapeutic target in heart failure. Here we investigated the potential effects of TT-00920, a clinical stage novel and highly selective PDE9 inhibitor, on heart failure in a rat model of myocardial infarction. Methods: Myocardial infarction was induced by left anterior descending coronary artery (LAD) ligation in male Sprague Dawley rats. After 4-week treatment of vehicle, LCZ696, TT-00920, or TT-00920/Valsartan by oral gavage, efficacy was assessed by echocardiography and cardiac histopathology. Results: TT-00920 had remarkably improved cardiac function, protected against cardiac remodeling and fibrosis in a dose-dependent manner. TT-00920/Valsartan combination showed superior beneficial efficacy when compared to TT-00920 or LCZ696 single agent.Figure 1. TT-00920 improved cardiac function and ventricular remodeling.Figure 2. TT-00920 attenuated cardiac fibrosis in peri-infarct zone. Conclusions: TT-00920 reversed LAD-induced left ventricular dysfunction and remodeling, supporting its potential as a novel therapeutic agent for heart failure. The superior efficacy of TT-00920/Valsartan combination suggests that TT-00920 and renin-angiotensin-aldosterone system inhibitors may have additive therapeutic effects in heart failure.TT-00920 is currently being evaluated in Phase 1 clinical study for safety, tolerability, pharmacokinetics and pharmacodynamics in healthy volunteers (NCT04364789).

Abstract 172: Lumican-null Mice Are Susceptible to Aging and Isoproterenol-induced Myocardial Fibrosis

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Pao-Hsien Chu
Keyword(s):  
Matrix Metalloproteinase ◽  
Atrial Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Myocardial Fibrosis ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Systolic Function ◽  
Wild Type ◽  
Matrix Metalloproteinase 1 ◽  
Membrane Type

Aims: With aging and stresses, the myocardium undergoes structural remodeling and often leading to fibrosis. Main Methods: To examine whether lumican, one of the class II small leucine-rich proteoglycans, has a role in cardiac remodeling and fibrosis, we analyzed the basic cardiac phenotypes of lumican-null (Lum-/-) mice in both youth and elder, and then used the isoproterenol-induced cardiac fibrosis model to study the roles of extra-cellular matrix and apoptosis in cardiac remodeling. Key Findings: Higher mortality resulted from significantly impaired systolic function, and an increase of atrial natriuretic peptide secreted by the ventricles in response to excessive stretching of myocytes of Lum-/- mice in comparison to wild type littermates. In addition, Lum-/- mice exhibited higher level of TGF-β, collagen I/III, and membrane-type matrix metalloproteinase-1 (MT1-MMP, or MMP-14) during cardiac remodeling. Significance: Our data implicates that the lumican protein plays an important role in the pathogenesis of cardiac fibrosis.

Determinants of cardiac fibrosis in experimental hypermineralocorticoid states

1995 ◽  
Vol 269 (4) ◽  
pp. E657-E662 ◽  
Author(s):  
M. Young ◽  
G. Head ◽  
J. Funder
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Fibrosis ◽  
Cardiac Effect ◽  
Mineralocorticoid Receptor Antagonist ◽  
Salt Loading ◽  
Blood Pressure Elevation ◽  
Intracerebroventricular Infusion ◽  
Ru 28318 ◽  
Primary Action ◽  
Drinking Solution

Uninephrectomized rats maintained on 1.0% NaCl to drink and infused with aldosterone (0.75 microgram/h) for 8 wk have previously been shown to develop hypertension, cardiac hypertrophy, and cardiac fibrosis. In the present study we have shown that K+ supplementation (1.0% NaCl plus 0.4% KCl drinking solution) alters neither the interstitial nor the perivascular fibrotic response to mineralocorticoid treatment. Second, rats receiving 0.75 microgram/h 9 alpha-fluorocortisol, a mineralocorticoid and glucocorticoid agonist, respond with hypertension and cardiac fibrosis without cardiac hypertrophy. Finally, intracerebroventricular infusion of the mineralocorticoid receptor antagonist RU-28318 blocks blood pressure elevation, but not cardiac hypertrophy or fibrosis, when aldosterone is coinfused peripherally. We conclude that the myocardial fibrosis observed in response to chronic mineralocorticoid elevation and salt loading is a humorally mediated event independent of hypokalemia, hypertension, and cardiac hypertrophy. It remains to be determined whether the fibrosis observed in the presence of excess salt represents a direct (e.g., cardiac) effect of mineralocorticoid hormones or one mediated via a primary action on classical epithelial aldosterone target tissues (e.g., kidney).

scholarly journals “(−)‐Epicatechin reduces inflammation biomarkers in plasma and ameliorates cardiac fibrosis in a female rat model of pre‐HFpEF”

2020 ◽  
Vol 34 (S1) ◽  
pp. 1-1
Author(s):  
Moises Muratt Bustamante-Pozo ◽  
Alejandra Alejandra Garate-Carrillo ◽  
FRANCISCO VILLARREAL ◽  
Bruce Robert Ito ◽  
GUILLERMO CEBALLOS ◽  
...  
Keyword(s):  
Rat Model ◽  
Cardiac Fibrosis ◽  
Female Rat
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