B009 Distinct gene regulation of two angiotensin-generating enzymes by angiotensin II in cardiac fibroblasts

Tanshinone IIA extracted from Danshen, a popular medicinal herb used in traditional Chinese medicine, exhibits cardio-protective effects. However, the mechanism of its cardioprotective effect is not well established. The aims of this study were to examine whether tanshinone IIA may alter angiotensin II (Ang II)-induced cell proliferation and to identify the putative underlying signaling pathways in rat cardiac fibroblasts. Cultured rat cardiac fibroblasts were pre-treated with tanshinone IIA and stimulated with Ang II, cell proliferation and endothelin-1 (ET-1) expression were examined. The effect of tanshinone IIA on Ang II-induced reactive oxygen species (ROS) formation, and extracellular signal-regulated kinase (ERK) phosphorylation were also examined. In addition, the effect of tanshinone IIA on nitric oxide (NO) production, and endothelial nitric oxide synthase (eNOS) phosphorylation were tested to elucidate the intracellular mechanism. The increased cell proliferation and ET-1 expression by Ang II (100 nM) were partially inhibited by tanshinone IIA. Tanshinone IIA also inhibited Ang II-increased ROS formation, and ERK phosphorylation. In addition, tanshinone IIA was found to increase the NO generation, and eNOS phosphorylation. NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NOS, and the short interfering RNA transfection for eNOS markedly attenuated the inhibitory effect of tanshinone IIA on Ang II-induced cell proliferation. The results suggest that tanshinone IIA prevents cardiac fibroblast proliferation by interfering with the generation of ROS and involves the activation of the eNOS-NO pathway.

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Angiotensin II Promotes Integrin-Mediated Collagen Gel Contraction by Adult Rat Cardiac Fibroblasts.

Japanese Heart Journal ◽

10.1536/jhj.40.461 ◽

1999 ◽

Vol 40 (4) ◽

pp. 461-469 ◽

Cited By ~ 16

Author(s):

Tatsuya NUNOHIRO ◽

Naoto ASHIZAWA ◽

Kristof GRAF ◽

Willa HSUEH ◽

Katsusuke YANO

Keyword(s):

Angiotensin Ii ◽

Cardiac Fibroblasts ◽

Collagen Gel ◽

Adult Rat ◽

Collagen Gel Contraction

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Abstract 478: FGF23 Expression in Cardiac Fibroblasts Is Augmented by S100/Calgranulins-Mediated Inflammation and Associated With Cardiac Hypertrophy, but Not in Angiotensin II-Induced Cardiac Hypertrophy

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.35.suppl_1.478 ◽

2015 ◽

Vol 35 (suppl_1) ◽

Author(s):

Marion Hofmann Bowman ◽

Brandon Gardner ◽

Judy Earley ◽

Debra L Rateri ◽

Alan Daugherty ◽

...

Keyword(s):

Angiotensin Ii ◽

Cardiac Hypertrophy ◽

Cardiac Fibroblasts ◽

Left Ventricular ◽

Heart Weight ◽

Ang Ii ◽

Wild Type ◽

Wild Type Littermate ◽

Transgenic Expression ◽

Significant Difference

Background: Serum S100A12 and fibroblast growth factor (FGF) 23 are biomarkers for cardiovascular mortality in patients with chronic kidney disease (CKD) and are associated with left ventricular hypertrophy (LVH). FGF23 is induced in cultured cardiac fibroblasts in response to cytokines including IL-6, TNF-a, LPS and S100/calgranulins. Moreover, hBAC-S100 transgenic mice with CKD had increased FGF23 in valvular interstitial cells and exhibited LVH. The present study was designed to examine cardiac FGF23 expression in other murine models of LVH in the absence of CKD. Methods: Hearts from five groups of male mice were studied: (i) C57BL6/J with transgenic expression a bacterial artificial chromosome of the human S100/calgranulins (S1008/9 and S100A12, hBAC-S100), (ii) wild type littermates, (iii) LDLR-/- infused with saline (29 days, 0.9%), (iv) LDLR-/- infused with angiotensin (Ang) II (29 days, 1000 ng/kg/min), and (v) fibroblast specific depletion of angiotensin II type 1a receptor (AT1aR) (S100A4-Cre x AT1aR-/- x LDLR-/-) infused with AngII. Results: hBAC-S100, but not wild type littermate mice, developed significant LVH at 10 months by heart weight/body weight (5.9 ±1.1 mg/g vs. 4.2 ±0.8, p<0.04), decreased E/A ratio, and increased LVPW thickness, and associated with increased expression of FGF23 mRNA and protein in cardiac tissue lysates (2-4 fold increase). Similarly, Ang II induced significant LVH compared to saline infused LDLR-/- mice (6.1±1.3 vs. 3.6 ±0.9 mg/g, p<0.01), and associated with increased mRNA for hypertrophic genes (ANP, BNP, b-MHC, CTGF and Col1a1). However, there was no significant difference in FGF23 mRNA and protein between Ang II and saline infused mice. Cardiac hypertrophy was attenuated in AngII-infused mice with deficiency of AT1aR (S100A4-Cre+/-xAT1aRxLDLR-/-). In vitro, Ang II (100nM) did not induce FGF23 in valvular interstitial fibroblasts or myocytes. Summary: Transgenic expression of S100/calgranulins is sufficient to induce LVH in aged mice with normal renal function, and this is associated with FGF23 expression in cardiac interstitial fibroblasts. Future studies are needed to determine whether cardiac FGF23 promotes LVH in a paracrine manner. However, FGF23 does not play a role in Ang II-induced LVH.

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Abstract 251: Mitochondrial Calcium Uniporter Regulates Proliferative Activity of Cardiac Fibroblasts Under Angiotensin II Stimulation

Circulation Research ◽

10.1161/res.125.suppl_1.251 ◽

2019 ◽

Vol 125 (Suppl_1) ◽

Author(s):

Bong S Jhun ◽

Yuta Suzuki ◽

Michael W Cypress ◽

Peng Zhang ◽

Ulrike Mende ◽

...

Keyword(s):

Angiotensin Ii ◽

Proliferative Activity ◽

Cardiac Fibroblasts ◽

Mitochondrial Calcium ◽

Mitochondrial Calcium Uniporter ◽

Calcium Uniporter

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Upregulation of α8β1-integrin in cardiac fibroblast by angiotensin II and transforming growth factor-β1

AJP Cell Physiology ◽

10.1152/ajpcell.2001.281.5.c1457 ◽

2001 ◽

Vol 281 (5) ◽

pp. C1457-C1467 ◽

Cited By ~ 32

Author(s):

Gaétan Thibault ◽

Marie-Josée Lacombe ◽

Lynn M. Schnapp ◽

Alexandre Lacasse ◽

Fatiha Bouzeghrane ◽

...

Keyword(s):

Angiotensin Ii ◽

Growth Factor ◽

Matrix Protein ◽

Transforming Growth Factor ◽

Cardiac Fibroblasts ◽

Transforming Growth Factor Β1 ◽

Cardiac Fibroblast ◽

Extracellular Matrix Protein ◽

Ang Ii ◽

Tgf Β1

Using a novel pharmacological tool with125I-echistatin to detect integrins on the cell, we have observed that cardiac fibroblasts harbor five different RGD-binding integrins: α8β1, α3β1, α5β1, αvβ1, and αvβ3. Stimulation of cardiac fibroblasts by angiotensin II (ANG II) or transforming growth factor-β1 (TGF-β1) resulted in an increase of protein and heightening by 50% of the receptor density of α8β1-integrin. The effect of ANG II was blocked by an AT1, but not an AT2, receptor antagonist, or by an anti-TGF-β1 antibody. ANG II and TGF-β1 increased fibronectin secretion, smooth muscle α-actin synthesis, and formation of actin stress fibers and enhanced attachment of fibroblasts to a fibronectin matrix. The α8- and β1-subunits were colocalized by immunocytochemistry with vinculin or β3-integrin at focal adhesion sites. These results indicate that α8β1-integrin is an abundant integrin on rat cardiac fibroblasts. Its positive modulation by ANG II and TGF-β1 in a myofibroblast-like phenotype suggests the involvement of α8β1-integrin in extracellular matrix protein deposition and cardiac fibroblast adhesion.

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