Inhibition of farnesyl pyrophosphate synthase attenuates angiotensin II-induced cardiac hypertrophy and fibrosis in vivo

2013 ◽  
Vol 45 (3) ◽  
pp. 657-666 ◽  
Author(s):  
Jian Yang ◽  
Huan-Huan Zhu ◽  
Guo-Ping Chen ◽  
Yang Ye ◽  
Chen-Ze Zhao ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Farnesyl Pyrophosphate ◽  
Farnesyl Pyrophosphate Synthase

Nitrogen-containing bisphosphonates can inhibit angiogenesis in vivo without the involvement of farnesyl pyrophosphate synthase

Bone ◽  
2011 ◽  
Vol 48 (2) ◽  
pp. 259-266 ◽  
Author(s):  
Verena Stresing ◽  
Pierrick G. Fournier ◽  
Akeila Bellahcène ◽  
Ismahène Benzaïd ◽  
Hannu Mönkkönen ◽  
...  
Keyword(s):  
Farnesyl Pyrophosphate ◽  
Farnesyl Pyrophosphate Synthase

scholarly journals Activation of autophagy during farnesyl pyrophosphate synthase inhibition is mediated through PI3K/AKT/mTOR signaling

2019 ◽  
Vol 48 (4) ◽  
pp. 030006051987537
Author(s):  
Jie Han ◽  
Chaoyang Huang ◽  
Jiukun Jiang ◽  
Dongmei Jiang
Keyword(s):  
Molecular Mechanisms ◽  
Cellular Proliferation ◽  
Umbilical Vein ◽  
Mtor Signaling ◽  
Farnesyl Pyrophosphate ◽  
Farnesyl Pyrophosphate Synthase ◽  
Acridine Orange Staining ◽  
Autophagy Induction

Objectives Autophagy is divided into three phases: autophagosome engulfment of intracellular organelles and proteins, autophagosome fusion with lysosomes, and autolysosome degradation. The farnesyl pyrophosphate synthase inhibitor ibandronate (IBAN) has in vivo cardioprotective properties, potentially via anti-oxidant effects. Whether autophagy is involved in the cardioprotective effect of IBAN remains unexplored. Methods Human umbilical vein endothelial cells (HUVECs) were treated in vitro with IBAN to assess autophagy induction. Lysosomal activation and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling were assessed using a LysoTracker assay, acridine orange staining and western blotting. An MTS assay was used to assess cellular proliferation. Autophagy was inhibited using chloroquine or RNA silencing of autophagy-related 7 (Atg7) expression. Results IBAN induced autophagy in HUVECs. Moreover, IBAN activated lysosomal function, which is pivotal to autophagy induction. PI3K/AKT/mTOR activity was inhibited in IBAN-treated HUVECs, indicating the involvement of this pathway in IBAN-induced autophagy. Inhibition of autophagy using either chloroquine or Atg7 siRNA potentiated inhibition of HUVEC growth by IBAN, suggesting the involvement of non-autophagy pathways in the antiproliferative effects of IBAN. Conclusions These findings provide insights into the role of autophagy in the cardioprotective effects of IBAN and the molecular mechanisms underlying autophagy induction by IBAN.

Cardiac-specific overexpression of diacylglycerol kinaseζ prevents angiotensin II-induced cardiac hypertrophy in vivo

2004 ◽  
Vol 10 (5) ◽  
pp. S151
Author(s):  
Arimoto Takanori ◽  
Takeishi Yasuchika ◽  
Takahashi Hiroki ◽  
Tetsuro Shishido ◽  
Takuya Miyamoto ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy

scholarly journals In Vivo Activities of Farnesyl Pyrophosphate Synthase Inhibitors against Leishmania donovani and Toxoplasma gondii

2002 ◽  
Vol 46 (3) ◽  
pp. 929-931 ◽  
Author(s):  
Vanessa Yardley ◽  
Anis A. Khan ◽  
Michael B. Martin ◽  
Teri R. Slifer ◽  
Fausto G. Araujo ◽  
...  
Keyword(s):  
Body Weight ◽  
Toxoplasma Gondii ◽  
Intravenous Administration ◽  
Leishmania Donovani ◽  
Effective Dosage ◽  
Farnesyl Pyrophosphate ◽  
Farnesyl Pyrophosphate Synthase

ABSTRACT The in vivo activities of three bisphosphonates were determined against Leishmania donovani and Toxoplasma gondii. Alendronate was essentially inactive against both parasites. Pamidronate was active against L. donovani by intravenous administration. Risedronate had a 50% effective dosage of five 2.6-mg/kg of body weight intraperitoneal doses against L. donovani-infected mice but was less effective against T. gondii-infected mice.

Abstract 470: Raf Kinase Inhibitors Activate ERK1/2 in Cardiomyocytes, Promoting Cardiac Hypertrophy in vitro and, in the Context of Angiotensin II-Induced Hypertension in Mice, in vivo

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Daniel N Meijles ◽  
Michelle A Hardyman ◽  
Stephen J Fuller ◽  
Kerry A Rostron ◽  
Sam J Leonard ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Kinase Inhibitors ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Internal Diameter ◽  
Dividing Cells ◽  
Lv Volume

Introduction: ERK1/2 promote hypertrophy and are protective in the heart, but cause cancer in dividing cells. Raf kinases lie upstream of ERK1/2 and Raf inhibitors (e.g. SB590885 (SB), dabrafenib (Dab)) are in development/use for cancer. Paradoxically, in cancer cells, low concentrations of SB/Dab stimulate (rather than inhibit) ERK1/2. Hypothesis: Our hypothesis is that the heart is primed for Raf paradox signaling. Raf inhibitors have potential to activate ERK1/2 in cardiomyocytes and promote cardiac hypertrophy. Methods: Neonatal rat ventricular cardiomyocytes (NRVMs) were exposed to inhibitors. Dab or SB (3 or 0.5 mg/kg/d) were studied in 12 wk male C57Bl6 mice in vivo in the presence of angiotensin II (AngII, 0.8 mg/kg/d) (n=6-11) using osmotic minipumps. Effects were compared with vehicle controls. Echocardiography was performed (Vevo2100). M-mode images (short axis view) were analyzed; data for each mouse were normalized to the mean of 2 baseline controls. Kinase activities were assessed by immunoblotting or in vitro kinase assays. Results: SB (0.1 μM) or Dab (1 μM) activated ERK1/2 (2.3±0.1 fold; n=4) in NRVMs consistent with Raf paradox signaling. An explanation is that Raf kinases dimerise and submaximal inhibitor concentrations bind one Raf protomer, locking it in an active conformation but activating the partner. In accord with this, 0.1 μM SB increased Raf activities. High SB concentrations (1-10 μM) initially inhibited ERK1/2 in NRVMs, but ERK1/2 were then activated (1 - 24 h) and promoted hypertrophy. In vivo (24 h), Dab and SB activated the ERK1/2 cascade, increasing ANF (17.3 ± 3.1 fold) and BNP (4.5 ± 0.8 fold) mRNA (n=4/5). Over 3 d, Dab and SB increased fractional shortening in the presence of AngII (1.22±0.06; 1.17±0.08), relative to AngII alone (0.95±0.04), increased systolic left ventricular (LV) wall thickness, and reduced systolic LV volume and internal diameter (0.83±0.03 cf 0.97±0.02 for AngII alone). Conclusions: The heart is primed for Raf paradox signaling and Raf inhibitors activate ERK1/2 in cardiomyocytes, promoting hypertrophy. In vivo, Raf inhibitors enhance ERK1/2 signaling and hypertrophy in the context of hypertension, and cardiac hypertrophy may be increased in hypertensive cancer patients receiving Raf inhibitors.

scholarly journals Heme Oxygenase-1 Inhibits Angiotensin II-Induced Cardiac Hypertrophy In Vitro and In Vivo

Circulation ◽  
2004 ◽  
Vol 110 (3) ◽  
pp. 309-316 ◽  
Author(s):  
Chien-Ming Hu ◽  
Yen-Hui Chen ◽  
Ming-Tsai Chiang ◽  
Lee-Young Chau
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Heme Oxygenase ◽  
Heme Oxygenase 1

scholarly journals (–)-Epicatechin Suppresses Angiotensin II-induced Cardiac Hypertrophy via the Activation of the SP1/SIRT1 Signaling Pathway

2017 ◽  
Vol 41 (5) ◽  
pp. 2004-2015 ◽  
Author(s):  
Zeng-xiang Dong ◽  
Lin Wan ◽  
Ren-jun Wang ◽  
Yuan-qi Shi ◽  
Guang-zhong Liu ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Signaling Pathway ◽  
Cardiomyocyte Hypertrophy ◽  
Ang Ii ◽  
Beneficial Effects ◽  
Protein Levels ◽  
Qrt Pcr

Background/Aims: Flavonol (–)-epicatechin (EPI) is present in high amounts in cocoa and tea products, and has been shown to exert beneficial effects on the cardiovascular system. However, the precise mechanism of EPI on cardiomyocyte hypertrophy has not yet been determined. In this study, we examined whether EPI could inhibit cardiac hypertrophy. Methods: We utilised cultured neonatal mouse cardiomyocytes and mice for immunofluorescence, immunochemistry, qRT-PCR, and western blot analyses. Results: 1µM EPI significantly inhibited 1µM angiotensin II (Ang II)-induced increase of cardiomyocyte size, as well as the mRNA and protein levels of ANP, BNP and β-MHC in vitro. The effects of EPI were accompanied with an up-regulation of SP1 and SIRT1, and were abolished by SP1 inhibition. Up-regulation of SP1 could block Ang II-induced increase in cardiomyocyte size, as well as the mRNA and protein levels of ANP, BNP and β-MHC, and increase the protein levels of SIRT1 in vitro. Moreover, 1 mg/kg body weight/day EPI significantly inhibited mouse cardiac hypertrophy induced by Ang II, which could be eliminated by SP1 inhibition in vivo. Conclusion: Our data indicated that EPI inhibited AngII-induced cardiac hypertrophy by activating the SP1/SIRT1 signaling pathway.

188 Calsarcin-1 inhibits Angiotensin-II induced cardiac hypertrophy in vivo and in vitro

2007 ◽  
Vol 6 (1) ◽  
pp. 44-45 ◽  
Author(s):  
D FRANK ◽  
C KUHN ◽  
M VANEICKELS ◽  
D GEHRING ◽  
H KATUS ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy
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