scholarly journals The Effects of 17-Methoxyl-7-Hydroxy-Benzene-Furanchalcone on Pressure Overload-Induced Cardiac Remodeling in Rats and the Endothelial Mechanisms Based on PGI2

2015 ◽  
Vol 36 (3) ◽  
pp. 1004-1014 ◽  
Author(s):  
Jianchun Huang ◽  
Xiaojun Tang ◽  
Xingmei Liang ◽  
Qingwei Wen ◽  
Shijun Zhang ◽  
...  
Keyword(s):  
Microvessel Density ◽  
Cardiac Remodeling ◽  
Sham Group ◽  
Cell Function ◽  
Colorimetric Method ◽  
Pressure Overload ◽  
Primary Objective ◽  
Heart Weight ◽  
Model Group ◽  
Endothelial Cell Function

Aim: The primary objective of this study was to study the effects of 17-methoxyl-7-hydroxy-benzene-furanchalcone (MHBFC) on pressure overload-induced cardiac remodeling in rats, as well as the endothelial mechanisms based on PGI2. Methods: Six weeks following surgery, rats were divided randomly into the following groups: a sham group, a model group, an MHBFC 12 mg/kg/day group (MHBFC 12), an indomethacin 2 mg/kg/day group (Indo 2), and an Indo 2+ MHBFC 12 group. The MS 4000 organism signal system was used to record the rats' hemodynamic indices. Additionally, the heart weight was determined, and the cardiac remodeling index was calculated. HE and Masson's stains were utilized to perform histological analyses; the immunofluorescence was used to observe the microvessel density of myocardial tissue; the colorimetric method was used to determine the hydroxyproline content of cardiac tissue; the ELISA method was used to measure the plasma PGI2 content; and transmission electron microscopy was used to observe the ultrastructure of the myocardium. Results: A hyperdynamic circulation state, cardiac remodeling, decreased microvessel density and decreased plasma PGI2 content were each observed in the model group compared with the sham group, in which any changes in the above parameters were effectively reversed by MHBFC. Single-use Indo administration resulted in the progression of these pathophysiological changes; however, MHBFC prevented the worsening of these parameters. Conclusion: MHBFC significantly reverses pressure overload-induced cardiac remodeling, and its mechanism may partially contribute to the amelioration of endothelial cell function and the augmentation of PGI2 synthesis and secretion.

scholarly journals Ventricular TLR4 Levels Abrogate TLR2-Knockout-Mediated Adverse Cardiac Remodeling upon Pressure Overload in Mice

2021 ◽  
Vol 22 (21) ◽  
pp. 11823
Author(s):  
Elise L. Kessler ◽  
Jiong-Wei Wang ◽  
Bart Kok ◽  
Maike A. Brans ◽  
Angelique Nederlof ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Cardiac Remodeling ◽  
Pressure Overload ◽  
Heart Weight ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Cross Sectional ◽  
Tlr4 Mrna ◽  
Tibia Length

Involvement of the Toll-like receptor 4 (TLR4) in maladaptive cardiac remodeling and heart failure (HF) upon pressure overload has been studied extensively, but less is known about the role of TLR2. Interplay and redundancy of TLR4 with TLR2 have been reported in other organs but were not investigated during cardiac dysfunction. We explored whether TLR2 deficiency leads to less adverse cardiac remodeling upon chronic pressure overload and whether TLR2 and TLR4 additively contribute to this. We subjected 35 male C57BL/6J mice (wildtype (WT) or TLR2 knockout (KO)) to sham or transverse aortic constriction (TAC) surgery. After 12 weeks, echocardiography and electrocardiography were performed, and hearts were extracted for molecular and histological analysis. TLR2 deficiency (n = 14) was confirmed in all KO mice by PCR and resulted in less hypertrophy (heart weight to tibia length ratio (HW/TL), smaller cross-sectional cardiomyocyte area and decreased brain natriuretic peptide (BNP) mRNA expression, p < 0.05), increased contractility (QRS and QTc, p < 0.05), and less inflammation (e.g., interleukins 6 and 1β, p < 0.05) after TAC compared to WT animals (n = 11). Even though TLR2 KO TAC animals presented with lower levels of ventricular TLR4 mRNA than WT TAC animals (13.2 ± 0.8 vs. 16.6 ± 0.7 mg/mm, p < 0.01), TLR4 mRNA expression was increased in animals with the largest ventricular mass, highest hypertrophy, and lowest ejection fraction, leading to two distinct groups of TLR2 KO TAC animals with variations in cardiac remodeling. This variation, however, was not seen in WT TAC animals even though heart weight/tibia length correlated with expression of TLR4 in these animals (r = 0.078, p = 0.005). Our data suggest that TLR2 deficiency exacerbates adverse cardiac remodeling and that ventricular TLR2 and TLR4 additively contribute to adverse cardiac remodeling during chronic pressure overload. Therefore, both TLRs may be therapeutic targets to prevent or interfere in the underlying molecular processes.

scholarly journals Protection of Sacubitril/Valsartan against Pathological Cardiac Remodeling by Inhibiting the NLRP3 Inflammasome after Relief of Pressure Overload in Mice

2020 ◽  
Vol 34 (5) ◽  
pp. 629-640
Author(s):  
Xueling Li ◽  
Qin Zhu ◽  
Qingcheng Wang ◽  
Qinggang Zhang ◽  
Yaru Zheng ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Pressure Overload ◽  
Myocardial Cell ◽  
Heart Weight ◽  
Inflammasome Activation ◽  
Clinical Prognosis ◽  
Nlrp3 Inflammasome Activation ◽  
Neprilysin Inhibitor

Abstract Background/aims The persistent existence of pathological cardiac remodeling, resulting from aortic stenosis, is related to poor clinical prognosis after successful transcatheter aortic valve replacement (TAVR). Sacubitril/valsartan (Sac/Val), comprising an angiotensin receptor blocker and a neprilysin inhibitor, has been demonstrated to have a beneficial effect against pathological cardiac remodeling, including cardiac fibrosis and inflammation in heart failure. The aim of this study was to determine whether Sac/Val exerts a cardioprotective effect after pressure unloading in mice. Methods and results Male C57BL/6 J mice were subjected to debanding (DB) surgery after 8 weeks (wk) of aortic banding (AB). Cardiac function was assessed by echocardiography, which indicated a protective effect of Sac/Val after DB. After treatment with Sac/Val post DB, decreased heart weight and myocardial cell size were observed in mouse hearts. In addition, histological analysis, immunofluorescence, and western blot results showed that Sac/Val attenuated cardiac fibrosis and inflammation after DB. Finally, our data indicated that Sac/Val treatment could significantly suppress NF-κB signaling and NLRP3 inflammasome activation in mice after relief of pressure overload. Conclusion Sac/Val exerted its beneficial effects to prevent maladaptive cardiac fibrosis and dysfunction in mice following pressure unloading, which was at least partly due to the inhibition of NLRP3 inflammasome activation.

Phase I dose escalation study of pomalidomide in combination with gemcitabine in patients (pts) with untreated metastatic carcinoma of the pancreas

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15539-e15539
Author(s):  
J. R. Infante ◽  
S. F. Jones ◽  
J. Bendell ◽  
D. Spigel ◽  
J. Barton ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Function ◽  
Metastatic Carcinoma ◽  
Primary Objective ◽  
Metastatic Pancreatic Cancer ◽  
Clinical Activity ◽  
Dose Escalation Study ◽  
Endothelial Cell Function ◽  
Grade 3 ◽  
Prophylactic Anticoagulation

e15539 Background: Pomalidomide is an IMiD immunomodulatory compound that is synergistic with gemcitabine in preclinical models. Pomalidomide has immuno-stimulatory properties and effects on the tumor microenvironment including inhibition of inflammatory mediators, stromal cell support, endothelial cell function, and angiogenesis. The primary objective is to determine the maximally tolerated dose (MTD) and evaluate the safety profile of pomalidomide in combination with gemcitabine. Methods: Eligibility included pts with untreated metastatic pancreatic cancer, adequate organ function, ECOG 0–1, and willingness to take prophylactic anticoagulation with aspirin, low-dose coumadin, or low molecular weight heparin. Gemcitabine 1,000 mg/m2 was given as a 30 min IV infusion on days 1, 8, and 15 of a 28 day cycle. Pomalidomide was given orally, daily for 21 days of a 28 day cycle. 3–6 pts were enrolled to increasing dose cohorts of pomalidomide (2, 3, 5, 7, and 10 mg/day) until dose-limiting toxicity (DLT) was seen in ≥2 of 6 pts. Results: As of 15-Dec-2008, 22 pts received ≥ 1 dose of pomalidomide. No DLT's were observed for 2–7 mg and 3 pts are currently on study in the 10 mg cohort. Neutropenia occurred in 12 pts, 8 were grade 3–4 events. There was 1 DLT of grade 3 neutropenic fever in the 10mg cohort. Thrombocytopenia events (9) were grade 1–2. Non- hematologic events were grade 1–2, the most common being rash (11), fatigue (10), nausea (6), and diarrhea (6). The rash is mild, erythematous, nonpruritic, of limited distribution, and reversible. 2 pts developed DVT (1 during cycle 2 and 1 cycle 4). Of the 16 pts evaluable for response, 1 pt has a confirmed PR and a CA 19–9 that normalized from 157 to <3. 4 additional pts have had minor radiographic responses between 10 and 29%. 10 of 16 pts have had a ≥ 60% decrease in CA19–9 from baseline. Only 2 pts came off study for early progression at the end of cycle 2. Conclusions: Dosing of pomalidomide daily for 21 days in combination with gemcitabine 1,000 mg/m2 given IV on day 1, 8, and 15 of a 28 day cycle was well tolerated and has promising clinical activity in patients with metastatic pancreatic cancer. The RP2D of pomalidomide in combination will be 7 or 10 mg. [Table: see text]

Abstract 536: Human Antigen R (HuR) in the Myofibroblasts is a Critical Regulator of Pressure-Overload Induced Cardiac Remodeling

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Lisa Green ◽  
Sarah Anthony ◽  
Perwez Alam ◽  
Michael Tranter
Keyword(s):  
Cardiac Function ◽  
Small Molecule ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Pressure Overload ◽  
Small Molecule Inhibitor ◽  
Heart Weight ◽  
Ecm Remodeling ◽  
Human Antigen R ◽  
Molecule Inhibitor

Cardiac fibrosis is characterized by the excessive deposition of extracellular matrix (ECM) and is an important target because excess ECM leads to a stiffened myocardium and worsens the prognosis of heart failure. Human Antigen R (HuR) is an RNA binding protein known to stabilize mRNA through binding to AU rich regions in the 3’UTR, and we have previously shown HuR to play a central role in the development of cardiac hypertrophy. To interrogate the role of HuR in cardiac fibrosis, we used both a small molecule inhibitor of HuR as well as an inducible genetic deletion of HuR in the activated cardiac myofibroblasts (iMF-HuR -/- ). Results using an in vitro scratch assay showed that primary adult cardiac fibroblasts treated with a small molecule inhibitor of HuR display a delayed wound healing response concomitant with a reduced expression of ECM remodeling genes. In vivo , we used an 8-week TAC (transverse aortic constriction) model of pressure overload to induce pathological cardiac remodeling. We hypothesized that deleting HuR in the activated fibroblasts would dampen myofibroblast-mediated ECM remodeling leading to a less stiff myocardium with reduced fibrotic burden and improved cardiac function in iMF-HuR -/- mice following pressure overload (TAC). However, echocardiography results show that cardiac function declined more rapidly in iMF-HuR -/- following TAC. The iMF-HuR -/- mice also had significantly enlarged hearts compared to the controls indicated by the heart weight/tibia length ratio. This suggests a critical role for HuR and myofibroblast activity in the early response to pressure overload. Future studies will focus on determining how the fibroblasts and the ECM composition/stiffness affect myocyte function in the early cardiac remodeling phase post-TAC and how HuR is involved in this relationship.

Do DPP-4 inhibitors improve endothelial cell function?

2017 ◽  
Vol 01 (01) ◽  
Author(s):  
Hiroshi Nomoto ◽  
Hideaki Miyoshi ◽  
Akinobu Nakamura ◽  
Tatsuya Atsumi ◽  
Naoki Manda ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Cell Function ◽  
Endothelial Cell Function

Estrogen Restores Endothelial Cell Function in an Experimental Model of Vascular Injury

Circulation ◽  
1997 ◽  
Vol 96 (5) ◽  
pp. 1624-1630 ◽  
Author(s):  
C. Roger White ◽  
Jonathan Shelton ◽  
Shi-Juan Chen ◽  
Victor Darley-Usmar ◽  
Leslie Allen ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Experimental Model ◽  
Vascular Injury ◽  
Cell Function ◽  
Endothelial Cell Function

scholarly journals CD40/CD40L contributes to hypercholesterolemia-induced microvascular inflammation

2009 ◽  
Vol 296 (3) ◽  
pp. H689-H697 ◽  
Author(s):  
Karen Y. Stokes ◽  
LeShanna Calahan ◽  
Candiss M. Hamric ◽  
Janice M. Russell ◽  
D. Neil Granger
Keyword(s):  
Oxidative Stress ◽  
T Cells ◽  
T Cell ◽  
Blood Cell ◽  
Cell Function ◽  
Inflammatory Responses ◽  
Microvascular Dysfunction ◽  
Cd40 Ligand ◽  
Scid Mice ◽  
Endothelial Cell Function

Hypercholesterolemia is associated with phenotypic changes in endothelial cell function that lead to a proinflammatory and prothrombogenic state in different segments of the microvasculature. CD40 ligand (CD40L) and its receptor CD40 are ubiquitously expressed and mediate inflammatory responses and platelet activation. The objective of this study was to determine whether CD40/CD40L, in particular T-cell CD40L, contributes to microvascular dysfunction induced by hypercholesterolemia. Intravital microscopy was used to quantify blood cell adhesion in cremasteric postcapillary venules, endothelium-dependent vasodilation responses in arterioles, and microvascular oxidative stress in wild-type (WT) C57BL/6, CD40-deficient (−/−), CD40L−/−, or severe combined immune deficient (SCID) mice placed on a normal (ND) or high-cholesterol (HC) diet for 2 wk. WT-HC mice exhibited an exaggerated leukocyte and platelet recruitment in venules and impaired vasodilation responses in arterioles compared with ND counterparts. A deficiency of CD40, CD40L, or lymphocytes attenuated these responses to HC. The HC phenotype was rescued in CD40L−/− and SCID mice by a transfer of WT T cells. Bone marrow chimeras revealed roles for both vascular- and blood cell-derived CD40 and CD40L in the HC-induced vascular responses. Hypercholesterolemia induced an oxidative stress in both arterioles and venules of WT mice, which was abrogated by either CD40 or CD40L deficiency. The transfer of WT T cells into CD40L−/− mice restored the oxidative stress. These results implicate CD40/CD40L interactions between circulating cells and the vascular wall in both the arteriolar and venular dysfunction elicited by hypercholesterolemia and identify T-cell-associated CD40L as a key mediator of these responses.

scholarly journals Investigation of Wall Shear Stress in Cardiovascular Research and in Clinical Practice—From Bench to Bedside

2021 ◽  
Vol 22 (11) ◽  
pp. 5635
Author(s):  
Katharina Urschel ◽  
Miyuki Tauchi ◽  
Stephan Achenbach ◽  
Barbara Dietel
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Wall Shear Stress ◽  
Cell Function ◽  
Computational Techniques ◽  
Apical Surface ◽  
Cardiovascular Research ◽  
Endothelial Cell Function ◽  
Wall Shear

In the 1900s, researchers established animal models experimentally to induce atherosclerosis by feeding them with a cholesterol-rich diet. It is now accepted that high circulating cholesterol is one of the main causes of atherosclerosis; however, plaque localization cannot be explained solely by hyperlipidemia. A tremendous amount of studies has demonstrated that hemodynamic forces modify endothelial athero-susceptibility phenotypes. Endothelial cells possess mechanosensors on the apical surface to detect a blood stream-induced force on the vessel wall, known as “wall shear stress (WSS)”, and induce cellular and molecular responses. Investigations to elucidate the mechanisms of this process are on-going: on the one hand, hemodynamics in complex vessel systems have been described in detail, owing to the recent progress in imaging and computational techniques. On the other hand, investigations using unique in vitro chamber systems with various flow applications have enhanced the understanding of WSS-induced changes in endothelial cell function and the involvement of the glycocalyx, the apical surface layer of endothelial cells, in this process. In the clinical setting, attempts have been made to measure WSS and/or glycocalyx degradation non-invasively, for the purpose of their diagnostic utilization. An increasing body of evidence shows that WSS, as well as serum glycocalyx components, can serve as a predicting factor for atherosclerosis development and, most importantly, for the rupture of plaques in patients with high risk of coronary heart disease.

scholarly journals Oxidative Stress as A Mechanism for Functional Alterations in Cardiac Hypertrophy and Heart Failure

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 931
Author(s):  
Anureet K. Shah ◽  
Sukhwinder K. Bhullar ◽  
Vijayan Elimban ◽  
Naranjan S. Dhalla
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Cardiac Remodeling ◽  
Cardiac Dysfunction ◽  
Critical Role ◽  
Pressure Overload ◽  
Hypertrophied Heart ◽  
Vasoactive Hormones

Although heart failure due to a wide variety of pathological stimuli including myocardial infarction, pressure overload and volume overload is associated with cardiac hypertrophy, the exact reasons for the transition of cardiac hypertrophy to heart failure are not well defined. Since circulating levels of several vasoactive hormones including catecholamines, angiotensin II, and endothelins are elevated under pathological conditions, it has been suggested that these vasoactive hormones may be involved in the development of both cardiac hypertrophy and heart failure. At initial stages of pathological stimuli, these hormones induce an increase in ventricular wall tension by acting through their respective receptor-mediated signal transduction systems and result in the development of cardiac hypertrophy. Some oxyradicals formed at initial stages are also involved in the redox-dependent activation of the hypertrophic process but these are rapidly removed by increased content of antioxidants in hypertrophied heart. In fact, cardiac hypertrophy is considered to be an adaptive process as it exhibits either normal or augmented cardiac function for maintaining cardiovascular homeostasis. However, exposure of a hypertrophied heart to elevated levels of circulating hormones due to pathological stimuli over a prolonged period results in cardiac dysfunction and development of heart failure involving a complex set of mechanisms. It has been demonstrated that different cardiovascular abnormalities such as functional hypoxia, metabolic derangements, uncoupling of mitochondrial electron transport, and inflammation produce oxidative stress in the hypertrophied failing hearts. In addition, oxidation of catecholamines by monoamine oxidase as well as NADPH oxidase activation by angiotensin II and endothelin promote the generation of oxidative stress during the prolonged period by these pathological stimuli. It is noteworthy that oxidative stress is known to activate metallomatrix proteases and degrade the extracellular matrix proteins for the induction of cardiac remodeling and heart dysfunction. Furthermore, oxidative stress has been shown to induce subcellular remodeling and Ca2+-handling abnormalities as well as loss of cardiomyocytes due to the development of apoptosis, necrosis, and fibrosis. These observations support the view that a low amount of oxyradical formation for a brief period may activate redox-sensitive mechanisms, which are associated with the development of cardiac hypertrophy. On the other hand, high levels of oxyradicals over a prolonged period may induce oxidative stress and cause Ca2+-handling defects as well as protease activation and thus play a critical role in the development of adverse cardiac remodeling and cardiac dysfunction as well as progression of heart failure.

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