scholarly journals Diastolic dysfunction is associated with cardiac fibrosis in the senescence-accelerated mouse

2011 ◽  
Vol 301 (3) ◽  
pp. H824-H831 ◽  
Author(s):  
Alana L. Reed ◽  
Atsuko Tanaka ◽  
Dan Sorescu ◽  
Hong Liu ◽  
Euy-Myoung Jeong ◽  
...  
Keyword(s):  
Growth Factor ◽  
Diastolic Dysfunction ◽  
Transforming Growth Factor ◽  
Diastolic Pressure ◽  
Diastolic Heart Failure ◽  
Left Ventricular ◽  
Tissue Growth ◽  
Doppler Imaging ◽  
Suitable Model ◽  
Samp8 Mice

Diastolic heart failure is a major cause of mortality in the elderly population. It is often preceded by diastolic dysfunction, which is characterized by impaired active relaxation and increased stiffness. We tested the hypothesis that senescence-prone (SAMP8) mice would develop diastolic dysfunction compared with senescence-resistant controls (SAMR1). Pulsed-wave Doppler imaging of the ratio of blood flow velocity through the mitral valve during early (E) vs. late (A) diastole was reduced from 1.3 ± 0.03 in SAMR1 mice to 1.2 ± 0.03 in SAMP8 mice ( P < 0.05). Tissue Doppler imaging of the early (E') and late (A') diastolic mitral annulus velocities found E' reduced from 25.7 ± 0.9 mm/s in SAMR1 to 21.1 ± 0.8 mm/s in SAMP8 mice and E'/A' similarly reduced from 1.1 ± 0.02 to 0.8 ± 0.03 in SAMR1 vs. SAMP8 mice, respectively ( P < 0.05). Invasive hemodynamics revealed an increased slope of the end-diastolic pressure-volume relationship (0.5 ± 0.05 vs. 0.8 ± 0.14; P < 0.05), indicating increased left ventricular chamber stiffness. There were no differences in systolic function or mean arterial pressure; however, diastolic dysfunction was accompanied by increased fibrosis in the hearts of SAMP8 mice. In SAMR1 vs. SAMP8 mice, interstitial collagen area increased from 0.3 ± 0.04 to 0.8 ± 0.09% and perivascular collagen area increased from 1.0 ± 0.11 to 1.6 ± 0.14%. Transforming growth factor-β and connective tissue growth factor gene expression were increased in the hearts of SAMP8 mice ( P < 0.05 for all data). In summary, SAMP8 mice show increased fibrosis and diastolic dysfunction similar to those seen in humans with aging and may represent a suitable model for future mechanistic studies.

Circulating Connective Tissue Growth Factor Is Associated with Diastolic Dysfunction in Patients with Diastolic Heart Failure

Cardiology ◽  
2019 ◽  
Vol 143 (3-4) ◽  
pp. 77-84 ◽  
Author(s):  
Hongjie Chi ◽  
Haijun Feng ◽  
Xiangyu Shang ◽  
Jie Jiao ◽  
Lanlan Sun ◽  
...  
Keyword(s):  
Heart Failure ◽  
Growth Factor ◽  
Connective Tissue ◽  
Diastolic Dysfunction ◽  
Connective Tissue Growth Factor ◽  
Transforming Growth Factor ◽  
Diastolic Heart Failure ◽  
Left Ventricular ◽  
Tissue Growth ◽  
Tgf Β1

Background: Connective tissue growth factor (CTGF) and transforming growth factor β1 (TGF-β1) are emerging biomarkers for tissue fibrosis. The aim of this study was to investigate the association between circulating CTGF, TGF-β1 levels and cardiac diastolic dysfunction in patients with diastolic heart failure (DHF). Methods: Admitted subjects were screened for heart failure and those with left ventricular (LV) ejection fraction <45% were excluded. Diastolic dysfunction was defined as functional abnormalities that exist during LV relaxation and filling by echocardiographic criteria. Totally 114 patients with DHF and 72 controls were enrolled. Plasma levels of CTGF, TGF-β1, and B-type natriuretic peptide (BNP) were determined. Results: The plasma CTGF and TGF-β1 levels increased significantly in patients with DHF. Circulating CTGF and TGF-β1 levels were correlated with echocardiographic parameter E/e’ and diastolic dysfunction grading in DHF patients. In multivariate logistic analysis, CTGF was significantly associated with diastolic dysfunction (odds ratio: 1.027, p < 0.001). Plasma CTGF (AUC: 0.770 ± 0.036, p < 0.001) and CTGF/BNP (AUC: 0.839 ± 0.036, p < 0.001) showed good predictive power to the diagnosis of DHF. Conclusions: This finding suggested CTGF could be involved in the pathophysiology of diastolic heart failure and CTGF/BNP might have auxiliary diagnostic value on diastolic heart failure.

scholarly journals Investigation of the Antihypertrophic and Antifibrotic Effects of Losartan in a Rat Model of Radiation-Induced Heart Disease

2021 ◽  
Vol 22 (23) ◽  
pp. 12963
Author(s):  
Mónika Gabriella Kovács ◽  
Zsuzsanna Z. A. Kovács ◽  
Zoltán Varga ◽  
Gergő Szűcs ◽  
Marah Freiwan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Heart Disease ◽  
Growth Factor ◽  
Rat Model ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Left Ventricular ◽  
Tissue Growth ◽  
Sprague Dawley ◽  
Radiation Induced

Radiation-induced heart disease (RIHD) is a potential late side-effect of thoracic radiotherapy resulting in left ventricular hypertrophy (LVH) and fibrosis due to a complex pathomechanism leading to heart failure. Angiotensin-II receptor blockers (ARBs), including losartan, are frequently used to control heart failure of various etiologies. Preclinical evidence is lacking on the anti-remodeling effects of ARBs in RIHD, while the results of clinical studies are controversial. We aimed at investigating the effects of losartan in a rat model of RIHD. Male Sprague-Dawley rats were studied in three groups: (1) control, (2) radiotherapy (RT) only, (3) RT treated with losartan (per os 10 mg/kg/day), and were followed for 1, 3, or 15 weeks. At 15 weeks post-irradiation, losartan alleviated the echocardiographic and histological signs of LVH and fibrosis and reduced the overexpression of chymase, connective tissue growth factor, and transforming growth factor-beta in the myocardium measured by qPCR; likewise, the level of the SMAD2/3 protein determined by Western blot decreased. In both RT groups, the pro-survival phospho-AKT/AKT and the phospho-ERK1,2/ERK1,2 ratios were increased at week 15. The antiremodeling effects of losartan seem to be associated with the repression of chymase and several elements of the TGF-β/SMAD signaling pathway in our RIHD model.

Abstract 17746: Telecinobufagin, a Novel Cardiotonic Steroid, Promotes Myocardial and Renal Fibrosis via Na/K-ATPase Profibrotic Signalling Pathways

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
David J Kennedy ◽  
Malory E Weber ◽  
Anuradha Guggilam ◽  
Kristen M Westfall ◽  
Brendan Agatisa-Boyle ◽  
...  
Keyword(s):  
Growth Factor ◽  
Renal Dysfunction ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Src Kinase ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Tissue Growth ◽  
Heart Weight

Cardiotonic steroids (CTS) are Na/K-ATPase (NKA) ligands that are elevated in volume-expanded states and associated with cardiac and renal dysfunction in both clinical and experimental settings. We recently discovered significantly elevated levels of a novel CTS, telocinobufagin (TCB), in patients with heart failure. We tested the hypothesis that TCB promotes cardiac and renal dysfunction in a process involving signaling through the NKA-α-1 in the following studies. First, we infused TCB (4 weeks at 10 ug/Kg/day) or vehicle into mice expressing wild type NKA-α-1 (WT), as well as mice with a genetic reduction of NKA-α-1 (NKA+/-) or transgenic human NKA-α-1 (NKA-Tg), which renders them more sensitive to CTS. TCB infusion resulted in impairment of cardiac structure (36% increase in heart weight/body weight ratio, 18% increase in diastolic Left Ventricular Internal Dimension vs. vehicle, p<0.05) in WT mice which was significantly attenuated in NKA+/- mice. TCB infusion also resulted increased proteinuria and cystatin C in WT mice which was significantly attenuated in NKA+/- mice (all p<0.05) despite similar increases in blood pressure. In NKA-Tg mice, TCB infusion resulted in increased myocardial (Fig 1A) and renal (Fig 1B) fibrosis vs. WT (all p<0.05). In a series of in vitro experiments, 24 hour treatment of HK2 renal proximal tubular cells with TCB resulted in significant dose dependent increases in both Collagen 1 and 3 mRNA (2 fold increases at 10 nM, 5 fold increases at 100 nM, p<0.05). TCB treatment (100 nM) of SYF fibroblasts reconstituted with cSrc resulted in a 1.5 fold increase in Collagen 1 and 3 mRNA (p<0.05) as well as increases in both Transforming Growth factor beta (TGFb, 1.5 fold, p<0.05) and Connective Tissue Growth Factor (CTGF, 2 fold, p<0.05), while these effects were absent in SYF cells without Src kinase. These studies suggest that the pro-fibrotic effects of TCB are mediated though the NKA-Src kinase signaling pathway.

P5442The non-steroidal mineralocorticoid receptor antagonist finerenone prevents structural cardiac remodeling

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
D Lavall ◽  
N Jacobs ◽  
F Mahfoud ◽  
P Kolkhof ◽  
M Boehm ◽  
...  
Keyword(s):  
Growth Factor ◽  
Left Atrial ◽  
Mineralocorticoid Receptor ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Left Ventricular ◽  
Tissue Growth ◽  
Neonatal Rat ◽  
Lv Function ◽  
Mineralocorticoid Receptor Antagonist

Abstract Background Mineralocorticoid receptor (MR) signaling mediates cardiac fibrosis. We studied the ability of the non-steroidal MR antagonist finerenone to prevent fibrotic remodeling. Methods and results In neonatal rat cardiac fibroblasts, finerenone prevented aldosterone-induced nuclear MR translocation. Treatment with finerenone decreased the expression of connective tissue growth factor (CTGF) (74±15% of control, p=0.005) and prevented aldosterone-induced upregulation of CTGF and lysyl oxidase (LOX) completely. Transforming growth factor β (TGF-β) upregulation induced through the Rac1 GTPase activator L-buthionine sulfoximine was attenuated by finerenone. Transgenic mice with cardiac-specific overexpression of Rac1 (RacET) showed increased left ventricular (LV) end-diastolic (63.7±8.0 vs. 93.8±25.6μl, p=0.027) and end-systolic (28.0±4.0 vs. 49.5±16.7μl, p=0.014) volumes compared to wild-type FVBN control mice. Treatment of RacET mice with 100ppm finerenone over 5 months prevented LV dilatation. Systolic and diastolic LV function was similarly preserved in the three groups. RacET mice exhibited overactivation of MR and 11β hydroxysteroid dehydrogenase type 2. Both effects were reduced by finerenone (reduction about 36%, p=0.030, and 40%, p=0.032, respectively). RacET mice demonstrated overexpression of TGF-β, CTGF, LOX as well as collagen and myocardial fibrosis in the left ventricle. In contrast, expression of these parameters did not differ between finerenone-treated RacET and control mice. Finerenone prevented left atrial dilatation (6.4±1.5 vs. 4.7±1.4mg, p=0.004) and left atrial fibrosis (17.8±3.1 vs. 12.8±3.1%, p=0.046) compared to vehicle-treated RacET mice. The prevalence of atrial arrhythmias at 5 months did not differ between finerenone- and vehicle-treated RacET mice. Conclusion Finerenone prevented from MR-mediated structural remodeling in cardiac fibroblasts and in RacET mice. These data demonstrate anti-fibrotic myocardial properties of finerenone.

scholarly journals JNK and p38 Inhibitors Prevent Transforming Growth Factor-β1-Induced Myofibroblast Transdifferentiation in Human Graves’ Orbital Fibroblasts

2021 ◽  
Vol 22 (6) ◽  
pp. 2952
Author(s):  
Tzu-Yu Hou ◽  
Shi-Bei Wu ◽  
Hui-Chuan Kau ◽  
Chieh-Chih Tsai
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Mapk Pathway ◽  
Transforming Growth Factor Β1 ◽  
Tissue Growth ◽  
Mitogen Activated Protein Kinase ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Western Blots ◽  
Orbital Fibroblasts ◽  
Tgf Β1

Transforming growth factor-β1 (TGF-β1)-induced myofibroblast transdifferentiation from orbital fibroblasts is known to dominate tissue remodeling and fibrosis in Graves’ ophthalmopathy (GO). However, the signaling pathways through which TGF-β1 activates Graves’ orbital fibroblasts remain unclear. This study investigated the role of the mitogen-activated protein kinase (MAPK) pathway in TGF-β1-induced myofibroblast transdifferentiation in human Graves’ orbital fibroblasts. The MAPK pathway was assessed by measuring the phosphorylation of p38, c-Jun N-terminal kinase (JNK), and extracellular-signal-regulated kinase (ERK) by Western blots. The expression of connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), and fibronectin representing fibrogenesis was estimated. The activities of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) responsible for extracellular matrix (ECM) metabolism were analyzed. Specific pharmacologic kinase inhibitors were used to confirm the involvement of the MAPK pathway. After treatment with TGF-β1, the phosphorylation levels of p38 and JNK, but not ERK, were increased. CTGF, α-SMA, and fibronectin, as well as TIMP-1 and TIMP-3, were upregulated, whereas the activities of MMP-2/-9 were inhibited. The effects of TGF-β1 on the expression of these factors were eliminated by p38 and JNK inhibitors. The results suggested that TGF-β1 could induce myofibroblast transdifferentiation in human Graves’ orbital fibroblasts through the p38 and JNK pathways.

scholarly journals Regulation of Cellular Senescence Is Independent from Profibrotic Fibroblast-Deposited ECM

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1628
Author(s):  
Kaj E. C. Blokland ◽  
Habibie Habibie ◽  
Theo Borghuis ◽  
Greta J. Teitsma ◽  
Michael Schuliga ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cellular Senescence ◽  
Transforming Growth Factor ◽  
Cell Function ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β1 ◽  
Tissue Growth ◽  
Alveolar Epithelial Cells ◽  
Lung Fibroblasts ◽  
Alpha Smooth Muscle Actin

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with poor survival. Age is a major risk factor, and both alveolar epithelial cells and lung fibroblasts in this disease exhibit features of cellular senescence, a hallmark of ageing. Accumulation of fibrotic extracellular matrix (ECM) is a core feature of IPF and is likely to affect cell function. We hypothesize that aberrant ECM deposition augments fibroblast senescence, creating a perpetuating cycle favouring disease progression. In this study, primary lung fibroblasts were cultured on control and IPF-derived ECM from fibroblasts pretreated with or without profibrotic and prosenescent stimuli, and markers of senescence, fibrosis-associated gene expression and secretion of cytokines were measured. Untreated ECM derived from control or IPF fibroblasts had no effect on the main marker of senescence p16Ink4a and p21Waf1/Cip1. However, the expression of alpha smooth muscle actin (ACTA2) and proteoglycan decorin (DCN) increased in response to IPF-derived ECM. Production of the proinflammatory cytokines C-X-C Motif Chemokine Ligand 8 (CXCL8) by lung fibroblasts was upregulated in response to senescent and profibrotic-derived ECM. Finally, the profibrotic cytokines transforming growth factor β1 (TGF-β1) and connective tissue growth factor (CTGF) were upregulated in response to both senescent- and profibrotic-derived ECM. In summary, ECM deposited by IPF fibroblasts does not induce cellular senescence, while there is upregulation of proinflammatory and profibrotic cytokines and differentiation into a myofibroblast phenotype in response to senescent- and profibrotic-derived ECM, which may contribute to progression of fibrosis in IPF.

Estimation of Left Ventricular Wall Stiffness by Analysis of Late Diastolic Pressure Components

2011 ◽  
Author(s):  
Casandra L. Niebel ◽  
Kelley C. Stewart ◽  
Takahiro Ohara ◽  
John J. Charonko ◽  
Pavlos P. Vlachos ◽  
...  
Keyword(s):  
Heart Failure ◽  
Left Ventricle ◽  
Diastolic Dysfunction ◽  
Diastolic Pressure ◽  
Left Ventricular Diastolic Dysfunction ◽  
Left Ventricular ◽  
Ventricular Wall ◽  
Ventricular Relaxation ◽  
Wall Stiffness ◽  
Ventricular Diastolic Dysfunction

Left ventricular diastolic dysfunction (LVDD) is any abnormality in the filling of the left ventricle and is conventionally evaluated by analysis of the relaxation driven phase, or early diastole. LVDD has been shown to be a precursor to heart failure and the diagnosis and treatment for diastolic failure is less understood than for systolic failure. Diastole consists of two filling waves, early and late and is primarily dependent on ventricular relaxation and wall stiffness.

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