Angiotensin II upregulates KCa3.1 channels and stimulates cell proliferation in rat cardiac fibroblasts

Wang, Liping; Wang, Yan; Zhao, Limei; Li, Gui-Rong; Deng, Xingming

doi:10.1016/j.bcp.2013.02.032

Cited by 44 publications

(34 citation statements)

References 36 publications

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“…23,30,31) In addition, p38 MAPK plays an important role in CF proliferation. 32,33) In this study, CFs showed a significant increase in p38 phosphorylation when treated with ISO, as compared with untreated controls. Both the p38 inhibitor SB202190 and DSS significantly reduced p38 phosphorylation and CF proliferation.…”

Section: Discussionmentioning

confidence: 48%

Danshensu Inhibits β-Adrenergic Receptors-Mediated Cardiac Fibrosis by ROS/p38 MAPK Axis

Tian

et al. 2014

Biological & Pharmaceutical Bulletin

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Danshensu, the effective ingredient of the plant Salvia miltiorrhiza (Danshen), has been widely used for treatment of cardiovascular diseases. Cardiac fibrosis is an important process in pathological cardiac remodeling and leads to heart failure. We investigated the effect of Danshensu on β-adrenergic receptor (β-AR)-mediated cardiac fibrosis and the involved signaling transduction. Danshensu inhibited cardiofibroblast proliferation and collagen I synthesis induced by isoproterenol (ISO), a selective β-AR agonist. Phosphorylation of p38 mitogen-activated protein kinase (MAPK), which mediates ISO-induced cardiac fibrosis, was negatively regulated in this process. The negative regulation depended on the ISO inhibition of reactive oxygen species (ROS) production. Taken together, Danshensu may inhibit β-AR-mediated cardiac fibrosis by negative regulation of ROS-p38 MAPK signaling.Key words Danshensu; β-adrenergic receptor; cardiac fibrosis; p38 MAPK; reactive oxygen specy Cardiac fibrosis is a pivotal phenomenon in pathological cardiac remodeling and is a hallmark of heart diseases. It is characterized by excessive extracellular matrix accumulation and fibroblast deposition and eventually destroys the organ architecture and abolishes normal function.1-3) Myocardial fibrosis is a major biological determinant of fatal events in cardiac remodeling, including heart failure, severe arrhythmias and sudden cardiac death.4,5) Cardiac fibrosis can be caused by various factors, such as the chronic activation of the sympathetic nervous system, myocardial hypoxia, ischemia, senescence, inflammation and hormones. β-Adrenergic receptors (β-ARs) and their associated guanine nucleotide regulatory protein (G protein)/adenylyl cyclase signal transduction pathways, are central to the regulation of cardiac function. Continuous activation of β-ARs plays an important role in cardiac dysfunction.6-8) Cardiac function was altered in β 1 -AR transgenic mice with cardiac hypertrophy, which could be inhibited by β-AR blockers.8) Consecutive administration with isoproterenol (ISO), a β-AR agonist, caused cardiac fibrosis in rats. 9,10) p38 mitogen-activated protein kinase (p38 MAPK) and reactive oxygen species (ROS) play a critical role in cardiac * To whom correspondence should be addressed. e-mail: lizijian@bjmu.edu.cn;zhengxh@nwu.edu.cnThe authors declare no conflict of interest. # These authors contributed equally to this work.

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Section: Discussionmentioning

confidence: 48%

Danshensu Inhibits β-Adrenergic Receptors-Mediated Cardiac Fibrosis by ROS/p38 MAPK Axis

Tian

et al. 2014

Biological & Pharmaceutical Bulletin

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“…Previous studies have shown that treatment with Ang II can activate ERK1/2 and NF-κB in cardiac fibroblasts [11,15] . In accordance with these studies, we observed that phospho-ERK1/2 and phospho-NF-κB-p65 were markedly upregulated in car- (Figure 3).…”

Section: Resultsmentioning

confidence: 99%

Effects of linagliptin and liraglutide on glucose- and angiotensin II-induced collagen formation and cytoskeleton degradation in cardiac fibroblasts in vitro

et al. 2016

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Aim: Glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors can not only lower blood glucose levels, but also alleviate cardiac remodeling after myocardial ischemia and hypertension. In the present study, we investigated the effects of a DPP-4 inhibitor (linagliptin) and a GLP-1 activator (liraglutide) on glucose-and angiotensin II (Ang II)-induced collagen formation and cytoskeleton reorganization in cardiac fibroblasts in vitro, and elucidated the related mechanisms. Methods: Cardiac fibroblasts were isolated from the hearts of 6-week-old C57BL/6 mice, and then exposed to different concentrations of glucose or Ang II for 24 h. The expression of fibrotic signals (fibronectin, collagen-1, -3 and -4), as well as ERK1/2 and NF-κB-p65 in the fibroblasts was examined using Western blotting assays. F-actin degradation was detected under inverted laser confocal microscope in fibroblasts stained with Rhodamine phalloidin. Results: Glucose (1-40 mmol/L) and Ang II (10-5 mol/L) dose-dependently increased the expression of fibronectin, collagens, phospho-ERK1/2 and phospho-NF-κB-p65 in cardiac fibroblasts. High concentrations of glucose (≥40 mmol/L) and Ang II (≥10 -6 mol/L) caused a significant degradation of F-actin (less assembly F-actin fibers and more disassembly fibers). ERK1/2 inhibitor U0126 (10 μmol/L) and NF-κB inhibitor JSH-23 (10 μmol/L) both markedly suppressed glucose-and angiotensin II-induced fibronectin and collagen expressions in cardiac fibroblasts. Furthermore, pretreatment with liraglutide (10-100 nmol/L) or linagliptin (3 and 30 nmol/L) significantly decreased glucose-and Ang II-induced expression of fibrotic signals, phospho-ERK1/2 and phospho-NF-κB-p65 in cardiac fibroblasts. Moreover, pretreatment with liraglutide (30 nmol/L) or liraglutide (100 nmol/L) markedly inhibited glucose-induced F-actin degradation, however, only liraglutide inhibited Ang II-induced F-actin degradation. Conclusion: Linagliptin and liraglutide inhibit glucose-and Ang II-induced collagen formation in cardiac fibroblasts via activation of the ERK/NF-κB/pathway. Linagliptin and liraglutide also markedly inhibit glucose-induced F-actin degradation in cardiac fibroblasts, but only liraglutide inhibits Ang II-induced F-actin degradation.

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“…Adult rat CFs were isolated and cultured using a modified procedure, as described previously [15]. Briefly, male Sprague-Dawley rats (8-12 weeks old) were anesthetized with sodium pentobarbital (50 mg/kg i.p.).…”

Section: Methodsmentioning

confidence: 99%

Erythropoietin Decreases the Occurrence of Myocardial Fibrosis by Inhibiting the NADPH-ERK-NF-κB Pathway

Wang¹,

Yang²,

Wang³

et al. 2015

Cardiology

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Objectives: The aim of this study was to investigate the protective role of erythropoietin (EPO) against myocardial fibrosis (MF). Methods: Pressure-overloaded rats were established by abdominal aortic constriction, the rats were randomly divided in a double-blind manner into 3 groups (n = 12 for each group): sham-operated rats (sham), operated rats receiving physiological saline (vehicle) and operated rats receiving 4,000 U/kg rhEPO (EPO group). The vehicle and drugs were administered to rats by intraperitoneal injection. In addition, cultured adult rat cardiac fibroblasts (CFs) were utilized to investigate the role of EPO in CF proliferation and collagen secretion. Results: After 4 weeks, besides an increase in blood pressure, myocardial hypertrophy, collagen deposition in the myocardium and decreased cardiac function were observed in the pressure-overloaded rats. The expression of NADPH oxidase (Nox2 and Nox4) and inflammatory cytokines (CD45, F4/80 and MCP-1) was also significantly increased. All these alterations were prevented by EPO. TGF-ß promoted CF proliferation, collagen secretion, ROS production and Nox2/Nox4 expression, which was inhibited by EPO. In addition, the TGF-ß-induced increase of ERK1/2 phosphorylation and NF-κB expression were attenuated by EPO. Conclusion: EPO inhibited rat MF induced by pressure overload and improved myocardial function by decreasing CF proliferation and differentiation via inhibition of the NADPH-ERK-NF-κB pathway.

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Angiotensin II upregulates KCa3.1 channels and stimulates cell proliferation in rat cardiac fibroblasts

Cited by 44 publications

References 36 publications

Danshensu Inhibits β-Adrenergic Receptors-Mediated Cardiac Fibrosis by ROS/p38 MAPK Axis

Danshensu Inhibits β-Adrenergic Receptors-Mediated Cardiac Fibrosis by ROS/p38 MAPK Axis

Effects of linagliptin and liraglutide on glucose- and angiotensin II-induced collagen formation and cytoskeleton degradation in cardiac fibroblasts in vitro

Erythropoietin Decreases the Occurrence of Myocardial Fibrosis by Inhibiting the NADPH-ERK-NF-κB Pathway

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