Pirfenidone Attenuates Cardiac Fibrosis in a Mouse Model of TAC-Induced Left Ventricular Remodeling by Suppressing NLRP3 Inflammasome Formation

Cardiology ◽  
2013 ◽  
Vol 126 (1) ◽  
pp. 1-11 ◽  
Author(s):  
Yongliang Wang ◽  
Yongquan Wu ◽  
Jiawei Chen ◽  
Shumei Zhao ◽  
Hongwei Li
Keyword(s):  
Mouse Model ◽  
Nlrp3 Inflammasome ◽  
Cardiac Fibrosis ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Left Ventricular

scholarly journals Low‐intensity Pulsed Ultrasound Ameliorates Angiotension Ii-induced Cardiac Fibrosisbyalleviating Inflammation via a Caveolin-1-dependent Pathway

2020 ◽  
Author(s):  
Kun Zhao ◽  
Jing Zhang ◽  
Tianhua Xu ◽  
Chuanxi Yang ◽  
Liqing Weng ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Fibrosis ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Left Ventricular ◽  
Pulsed Ultrasound ◽  
Caveolin 1 ◽  
Low Intensity Pulsed Ultrasound

Abstract Background: Cardiac hypertrophy and fibrosis are major pathological manifestations observed in left ventricular remodeling induced by Angiotensin II (AngII). Concerning the fact that low‐intensity pulsed ultrasound (LIPUS) has been reported to improve cardiac dysfunction and myocardial fibrosis in myocardial infarction (MI) through mechanotransductionanditsdownstream pathways, we aimed to investigate whether LIPUS could also exert a protective effect on ameliorating AngII-induced cardiac hypertrophy and fibrosis andand if so, to further elucidate the underlying molecular mechanisms.Methods: In our study, we used AngII to mimic the animal and cell culture models of cardiac hypertrophy and fibrosis, where LIPUS irradiation (0.5MHz, 77.20mW/cm2) was applied for 20 minutes every 2 days from 1 week before surgery to 4 weeks after surgery in vivo, and every 6 hours for a total of 2 times in vitro. Following that, the levels of cardiac hypertrophy and fibrosis were evaluated by echocardiographic, histopathological, and molecular biological methods. Results: Our results showed that LIPUS irradiation could ameliorate left ventricular remodeling in vivo and cardiac fibrosis in vitro by reducing AngII-inducedrelease of inflammatory cytokines, while the protective effects were limited on cardiac hypertrophy in vitro. Given that LIPUS irradiation increased the expression of caveolin-1 related to mechanical stimulation, we inhibited caveolin-1 activity with pyrazolopyrimidine 2 (pp2) in vitro, by which LIPUS-induced downregulation of inflammation was reversed and the anti-fibrosis effects of LIPUS irradiation were absent. Conclusions: Taken together, these results indicate that LIPUS irradiation could ameliorate AngII-induced cardiac fibrosis by alleviating inflammation via a caveolin-1-dependent pathway, providing new insights for the development of novel therapeuticapparatus in clinical practice.

Abstract P300: Cardiac Ly6C high Monocyte Accumulation and Remodeling Depend on the Mineralocorticoid Receptor in Endothelial Cells

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Achim Lother ◽  
Aurelia Hübner ◽  
Ingo Hilgendorf ◽  
Tilman Schnick ◽  
Martin Moser ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Diastolic Dysfunction ◽  
Mineralocorticoid Receptor ◽  
Cardiac Fibrosis ◽  
Ventricular Remodeling ◽  
Interstitial Fibrosis ◽  
Left Ventricular Remodeling ◽  
Marker Gene ◽  
Pressure Overload ◽  
Left Ventricular

Introduction: Inflammation is a key driver for the development of cardiac fibrosis and diastolic dysfunction. Aldosterone promotes the expression of adhesion molecules and vascular inflammation. Thus, the goal of the present study was to examine the significance of endothelial MR for pressure overload induced cardiac inflammation and remodeling. Methods and results: Mice with endothelial cell-specific deletion of the mineralocorticoid receptor (MR Cdh5Cre ) were generated using the Cre/loxP system. MR Cdh5Cre and Cre-negative littermates (MR wildtype ) underwent transverse aortic constriction (TAC, n=5-7 per group). After two weeks of pressure overload echocardiography revealed diastolic dysfunction in MR wildtype (mitral valve E acceleration time TAC 15.7 ± 0.5 vs. sham 12.8 ± 0.4 ms, P<0.05) but not in MR Cdh5Cre mice (TAC 11.2 ± 0.6 vs. sham 12.2 ± 0.9 ms, n.s.). Cardiac hypertrophy (ventricle weight 143.2 ± 5.2 vs. MR wildtype 167.3 ± 6.7 mg, P<0.001) and interstitial fibrosis (sirius red stained area 8.2 ± 4.7 vs. MR wildtype 13.5 ± 4.5 %, P<0.05) following TAC were attenuated in MR Cdh5Cre mice. mRNA expression of atrial natriuretic peptide ( Nppa , 2429 ± 1230 vs. MR wildtype 7051 ± 3182 copies/10 4 copies Rps29 , P<0.01) or the fibrosis marker gene collagen 1a1 ( Col1a1 , 256 ± 89 vs. MR wildtype 432 ± 165 copies/10 4 copies Rps29 , P<0.05) as determined by qRT-PCR confirmed these findings. Cardiac leukocytes were quantitatively analyzed by fluorescence assisted cell sorting using specific antibodies. Numbers of CD45 + leukocytes were similarly increased after TAC in the hearts of both genotypes (MR Cdh5Cre 3840 ± 443 vs. MR wildtype 4051 ± 385 /mg tissue, n.s.). Subtype analysis revealed a shift towards CD45 + CD11b + F4/80 low Ly6C high monocytes vs. CD45 + CD11b + F4/80 high Ly6C low macrophages in the heart of MR wildtype (TAC 20 ± 6 vs. sham 4 ± 1 % of CD45 + CD11b + , P<0.05) but not of MR Cdh5Cre mice (TAC 6 ± 2 vs. sham 3 ± 1 % of CD45 + CD11b + , n.s.). Conclusion: MR deletion from endothelial cells ameliorates left ventricular remodeling and diastolic dysfunction after pressure overload. The protective effect of endothelial MR deletion is associated with a shift towards less pro-inflammatory Ly6C high monocytes and more reparative Ly6C low macrophages.

scholarly journals Blockade of KCa3.1 Attenuates Left Ventricular Remodeling after Experimental Myocardial Infarction

2015 ◽  
Vol 36 (4) ◽  
pp. 1305-1315 ◽  
Author(s):  
Chen-Hui Ju ◽  
Xian-Pei Wang ◽  
Chuan-Yu Gao ◽  
Shuang-Xia Zhang ◽  
Xing-Hua Ma ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Fibrosis ◽  
Ventricular Remodeling ◽  
Heart Function ◽  
Left Ventricular Remodeling ◽  
Left Ventricular ◽  
Experimental Myocardial Infarction ◽  
Ang Ii ◽  
Pharmacological Blockade

Background/Aims: After myocardial infarction (MI), cardiac fibrosis greatly contributes to left ventricular remodeling and heart failure. The intermediate-conductance calcium-activated potassium Channel (KCa3.1) has been recently proposed as an attractive target of fibrosis. The present study aimed to detect the effects of KCa3.1 blockade on ventricular remodeling following MI and its potential mechanisms. Methods: Myocardial expression of KCa3.1 was initially measured in a mouse MI model by Western blot and real time-polymerase chain reaction. Then after treatment with TRAM-34, a highly selective KCa3.1 blocker, heart function and fibrosis were evaluated by echocardiography, histology and immunohistochemistry. Furthermore, the role of KCa3.1 in neonatal mouse cardiac fibroblasts (CFs) stimulated by angiotensin II (Ang II) was tested. Results: Myocardium expressed high level of KCa3.1 after MI. Pharmacological blockade of KCa3.1 channel improved heart function and reduced ventricular dilation and fibrosis. Besides, a lower prevalence of myofibroblasts was found in TRAM-34 treatment group. In vitro studies KCa3.1 was up regulated in CFs induced by Ang II and suppressed by its blocker.KCa3.1 pharmacological blockade attenuated CFs proliferation, differentiation and profibrogenic genes expression and may regulating through AKT and ERK1/2 pathways. Conclusion: Blockade of KCa3.1 is able to attenuate ventricular remodeling after MI through inhibiting the pro-fibrotic effects of CFs.

scholarly journals Speckle Tracking Echocardiography Verified the Efficacy of Qianyangyuyin Granules in Alleviating Left Ventricular Remodeling in a Hypertensive Rat Model

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Anxia He ◽  
Lijun Qian ◽  
Shihai Yan ◽  
Menglin Zhu ◽  
Xixuan Zhao ◽  
...  
Keyword(s):  
Rat Model ◽  
Speckle Tracking ◽  
Cardiac Fibrosis ◽  
Ventricular Remodeling ◽  
Speckle Tracking Echocardiography ◽  
Volume Fraction ◽  
Left Ventricular Remodeling ◽  
Left Ventricular ◽  
Collagen Volume Fraction ◽  
Hypertensive Rat

Background. Global longitudinal strain (GLS) can be assessed by speckle tracking echocardiography (STE) to express the degree of cardiac fibrosis. Qianyangyuyin (QYYY) granules can effectively improve GLS in hypertensive patients. Using a hypertensive rat model, we carried out speckle tracking echocardiography to validate the effect of QYYY in diminishing LV remodeling. Methods. We randomly divided 16 spontaneously hypertensive rats (SHRs) into SHR, SHR + valsartan (SHR + V), SHR + low-dose QYYY (SHR + QL), and SHR + high-dose QYYY (SHR + QH) groups, with four rats in each group. Another group of 4 Wistar-Kyoto (WKY) rats were selected into a normal control (WKY) group. At the 8th week, conventional echocardiographic parameters were measured by GE Vivid E95 ultrasound (12S probe, 10–12 MHz) and GLS by speckle tracking echocardiography with EchoPAC (version 203) software. HE and Masson’s trichrome staining were performed to detect the cardiomyocyte width and collagen volume fraction after rat sacrifice. Collagen I, α-SMA, S100A4, TGF-β, Smad 3, MYH6, and MYH7 were further analyzed by Western blot. Results. The absolute values of GLS significantly increased in the SHR + QH group compared to the SHR group, while the CVF and CW values significantly decreased. In addition, Collagen I, α-SMA, S100A4, TGF-β, Smad3, MYH7, and MYH7/MYH6 ratio remarkably reduced in the SHR + QH group. The value of GLS could be repetitively measured and positively correlated with the collagen volume fraction of the myocardium and the cardiomyocyte width of the left ventricular free wall. Conclusions. GLS is a reliable indicator to evaluate the therapeutic effect on left ventricular remodeling in hypertension. QYYY granules can inhibit the development of cardiac fibrosis in the hypertensive rat model.

Abstract 169: Angiotensin-II Induced Left Ventricular Remodeling Differs Between C57bl/6 Substrains

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Sophie Cardin ◽  
Marie-Pier Scott-Boyer ◽  
Sylvie Picard ◽  
Tim L Reudelhuber ◽  
Christian F Deschepper
Keyword(s):  
Gene Expression ◽  
Angiotensin Ii ◽  
Cardiac Fibrosis ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Left Ventricular ◽  
Cardiovascular Research ◽  
Lv Remodeling ◽  
Fold Induction ◽  
Subsequent Activation

Background: Although C57Bl/6 mice are widely used in cardiovascular research, little is known about possible substrain differences. We compared the left ventricular (LV) remodeling induced by angiotensin II (angII) in C57Bl/6J and C57Bl/6N mice, these 2 substrains corresponding to two main branches having diverged since 1951. Methods and Results: Male C57Bl/6J and C57Bl/6N mice were treated with angII (350ng/kg/min) or vehicle via mini-osmotic pumps for either 48h (for microarray profiling of gene expression and macrophage cytofluorometry counting) or 15 days (for both gene expression and histology). AngII (15d) induced fibrosis in LV from C57BL/6N (as shown by histology and col1a expression), but not in C57BL/6J. After 48h of treatment, about 100 genes responded in a strain-specific fashion, most responses being specific for C57Bl/6N mice. Among genes showing greater than 2-fold induction by angII (48h) in C57Bl/6N mice, there was enrichment for markers of macrophages activation and M2 polarization (including osteopontin, arginase1 and galectin3). These strain-specific differences were confirmed (both in LV tissues and macrophages isolated from LVs) by Q-RT-PCR, and occurred despite that fact that AngII increased the abundance of Cd11b+ macrophages to the same extent in both strains. Moreover, AngII (48h) increased expression of several markers of fibroblast activation (including Timp1, Lox and tenascin) in C57Bl/6N (both in LV tissue and fibroblasts isolated from LVs), but not in C57Bl/6J. Although one of the best known genetic differences in both substrains is the inactivation of the Nnt gene in C57Bl6/J mice, experiments performed in F2 mice do not indicate that the fibrotic response co-segregates with the Nnt mutation. Conclusions: Although angII-treatment induces macrophage recruitment in the LVs of both C57Bl/6J and C57Bl/6N mice, activation of cardiac macrophages and their M2 pro-reparative polarization (with subsequent activation of fibroblasts and synthesis of collagen) occurs only in the genetic C57Bl/6N background. The absence of macrophage activation and cardiac fibrosis in C57BL/6J may possibly explain some differences in experimental results obtained by various investigators using different C57BL/6 substrains.

scholarly journals A novel cardiac muscle-derived biomaterial reduces dyskinesia and postinfarct left ventricular remodeling in a mouse model of myocardial infarction

2015 ◽  
Vol 3 (3) ◽  
pp. e12351 ◽  
Author(s):  
Daniel M. O'Connor ◽  
Nivedita K. Naresh ◽  
Bryan A. Piras ◽  
Yaqin Xu ◽  
Robert S. Smith ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Mouse Model ◽  
Cardiac Muscle ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Left Ventricular

scholarly journals Decreased metalloprotease 9 induction, cardiac fibrosis, and higher autophagy after pressure overload in mice lacking the transcriptional regulator p8

2011 ◽  
Vol 301 (5) ◽  
pp. C1046-C1056 ◽  
Author(s):  
Serban P. Georgescu ◽  
Mark J. Aronovitz ◽  
Juan L. Iovanna ◽  
Richard D. Patten ◽  
John M. Kyriakis ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Fibrosis ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Pressure Overload ◽  
Transcriptional Regulator ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Causative Role

Left ventricular remodeling, including the deposition of excess extracellular matrix, is key to the pathogenesis of heart failure. The stress-inducible transcriptional regulator p8 is increased in failing human hearts and is required both for agonist-stimulated cardiomyocyte hypertrophy and for cardiac fibroblasts matrix metalloprotease-9 (MMP9) induction. In the heart, upregulation of autophagy is an adaptive response to stress and plays a causative role in cardiomyopathies. We have recently shown that p8 ablation in cardiac cells upregulates autophagy and that, in vivo, loss of p8 results in a decrease of cardiac function. Here we investigated the effects of p8 genetic deletion in mediating adverse myocardial remodeling. Unstressed p8−/− mouse hearts manifested complex alterations in the expression of fibrosis markers. In addition, these mice displayed elevated autophagy and apoptosis compared with p8+/+ mice. Transverse aortic constriction (TAC) induced left ventricular p8 expression in p8+/+ mice. Pressure overload caused left ventricular remodeling in both genotypes, however, p8−/− mice showed less cardiac fibrosis induction. Consistent with this, although MMP9 induction was attenuated in the p8−/− mice, induction of MMP2 and MMP3 were strikingly upregulated while TIMP2 was downregulated. Left ventricular autophagy increased after TAC and was significantly higher in the p8−/− mice. Thus p8-deletion results in reduced collagen fibrosis after TAC, but in turn, is associated with a detrimental higher increase in autophagy. These findings suggest a role for p8 in regulating in vivo key signaling pathways involved in the pathogenesis of heart failure.

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