Abstract 076: Lapatinib Reduced Cardiac Hypertrophy Induced By Combined Use Of A Pi3k-mtor Dual Inhibitor And Doxorubicin

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Xinhua Yan ◽  
Yongyao Yang ◽  
Juyong Lee ◽  
Jillian Onufrak ◽  
John Fuseler ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Effect ◽  
Mtor Pathway ◽  
Dual Inhibitor ◽  
Cardiac Side Effects ◽  
Compound C ◽  
Transmission Electron ◽  
Combined Use ◽  
Cardioprotective Effects ◽  
Lapatinib Treatment

The HER2-PI3K-mTOR pathway is pivotal for regulating the physiological function of the heart. Currently, drugs targeting the HER2-PI3K-mTOR pathway are either approved or being tested in clinical trials for cancer therapy. It is, therefore, important to evaluate the cardiac effects of using these drugs. In addition, it is necessary to develop countermeasures to prevent the cardiac side effects if any. Methods: Three-month old female FVB/n mice were treated with lapatinib (an HER2 inhibitor) or BEZ235 (BEZ, a PI3K-mTOR dual inhibitor), alone or with doxorubicin (DOX). Cardiac function was monitored by echocardiography and hemodynamic measurements. Cardiac morphology was assessed by confocal microscopy and transmission electron microscopy. The activation of signaling molecules were measured by Western blot analysis. Results: BEZ alone induced cardiac hypertrophy and subsequent heart failure and lapatinib alone induced cardiac failure, in a course of 17 months, respectively. Combination of BEZ with DOX, either concurrently or sequentially, induced cardiac hypertrophy which was associated with higher mortality rate compared to DOX alone. Neuregulin1, a HER receptor ligand worsened, while Lapatinib alleviated, cardiac hypertrophy in these mice. Lapatinib increased the activation of AMPK in DOX+BEZ treated hearts. The cardiac effect of lapatinib was blocked by Compound C, an AMPK inhibitor. Metformin, an AMPK activator, alleviated DOX+BEZ induced cardiac hypertrophy. Conclusions: BEZ or lapatinib treatment alone induced irreversible cardiac dysfunction in mice. Combined use of BEZ and DOX induced cardiac hypertrophy and early mortality, which were prevented by lapatinib. The cardioprotective effects of lapatinib may rely on activating AMPK in the heart.

Combined Use of a PI3K-mTOR Dual Inhibitor and Doxorubicin Induced Cardiac Hypertrophy and Early Death in Mice

2013 ◽  
Vol 19 (8) ◽  
pp. S67
Author(s):  
Xinhua Yan ◽  
Yongyao Yang ◽  
Juyong Lee ◽  
Jillian Onufrak ◽  
Sharath Sasi ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Early Death ◽  
Dual Inhibitor ◽  
Combined Use

GPR39 promotes cardiac hypertrophy by regulating the AMPK‐mTOR pathway and protein synthesis

2021 ◽  
Author(s):  
Hongjuan Liao ◽  
Weinian Gao ◽  
Jie Ma ◽  
Hongyuan Xue ◽  
Yi Wang ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Cardiac Hypertrophy ◽  
Mtor Pathway

NLRC5 enhances autophagy via inactivation of AKT/mTOR pathway and ameliorates cardiac hypertrophy

2021 ◽  
Author(s):  
Bayinsilema Ba ◽  
Abudoukelimu Mayila ◽  
Yankai Guo ◽  
Jie Xu ◽  
Shifeng Xing ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Mtor Pathway

Omentin-1 attenuates glucocorticoid-induced cardiac injury by phosphorylating GSK3β

2021 ◽  
Vol 66 (4) ◽  
pp. 273-283
Author(s):  
Zhousheng Jin ◽  
Fangfang Xia ◽  
Jiaojiao Dong ◽  
Tingting Lin ◽  
Yaoyao Cai ◽  
...  
Keyword(s):  
Side Effects ◽  
Cardiac Hypertrophy ◽  
Cardiac Injury ◽  
Experimental Studies ◽  
Chronic Administration ◽  
Cardiovascular Complications ◽  
Rat Serum ◽  
Cardiac Side Effects ◽  
Beneficial Effects

Glucocorticoid excess often causes a variety of cardiovascular complications, including hypertension, atherosclerosis, and cardiac hypertrophy. To abrogate its cardiac side effects, it is necessary to fully disclose the pathophysiological role of glucocorticoid in cardiac remodelling. Previous clinical and experimental studies have found that omentin-1, one of the adipokines, has beneficial effects in cardiovascular diseases, and is closely associated with metabolic disorders. However, there is no evidence to address the potential role of omentin-1 in glucocorticoid excess-induced cardiac injuries. To uncover the links, the present study utilized rat model with glucocorticoid-induced cardiac injuries and clinical patients with abnormal cardiac function. Chronic administration of glucocorticoid excess reduced rat serum omentin-1 concentration, which closely correlated with cardiac functional parameters. Intravenous administration of adeno-associated virus encoding omentin-1 upregulated the circulating omentin-1 level and attenuated glucocorticoid excess-induced cardiac hypertrophy and functional disorders. Overexpression of omentin-1 also improved cardiac mitochondrial function, including the reduction of lipid deposits, induction of mitochondrial biogenesis, and enhanced mitochondrial activities. Mechanistically, omentin-1 phosphorylated and activated the GSK3β pathway in the heart. From a study of 28 patients with Cushing’s syndrome and 23 healthy subjects, the plasma level of glucocorticoid was negatively correlated with omentin-1, and was positively associated with cardiac ejection fraction and fractional shortening. Collectively, the present study provided a novel role of omentin-1 in glucocorticoid excess-induced cardiac injuries and found that the omentin-1/GSK3β pathway was a potential therapeutic target in combating the side effects of glucocorticoid.

scholarly journals ROS Promote Ox-LDL-Induced Platelet Activation by Up-Regulating Autophagy Through the Inhibition of the PI3K/AKT/mTOR Pathway

2018 ◽  
Vol 50 (5) ◽  
pp. 1779-1793 ◽  
Author(s):  
Xiang Wang ◽  
Yun-Feng Fu ◽  
Xiao Liu ◽  
Guo Feng ◽  
Dan Xiong ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Platelet Aggregation ◽  
Platelet Activation ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Mtor Pathway ◽  
Enhanced Chemiluminescence ◽  
Transmission Electron ◽  
Related Proteins

Background/Aims: Oxidized low-density lipoprotein (oxLDL) promotes unregulated platelet activation in patients with dyslipidemic disorders. Although oxLDL stimulates activating signaling, researchers have not clearly determined how these events drive accelerated thrombosis. Here, we describe the mechanism by which ROS regulate autophagy during ox-LDL-induced platelet activation by modulating the PI3K/AKT/mTOR signaling pathway. Methods: For in vitro experiments, ox-LDL, the ROS scavenger N-acetylcysteine (NAC), the mTOR inhibitor rapamycin and the autophagy inhibitor 3-MA were used alone or in combination with other compounds to treat platelets. Then, platelet aggregation was evaluated on an aggregometer and platelet adhesion was measured under shear stress. The levels of a platelet activation marker (CD62p) were measured by flow cytometry, reactive oxygen species (ROS) levels were then quantified by measuring DCFH-DA fluorescence intensity via flow cytometry. Nitric oxide (NO) and superoxide (O2·-) levels were determined by the nitric acid deoxidize enzyme method and lucigenin-enhanced chemiluminescence (CL), respectively. Transmission electron microscopy was used to observe the autophagosome formation, immunofluorescence staining was employed to detect LC3 expression and western blotting was used to measure the levels of PI3K/AKT/mTOR pathway- and autophagy-related proteins. Results: Ox-LDL-induced platelets showed a significant increase in platelet aggregation and adhesion, CD62p expression, ROS level and O2·- content, with an elevated LC3II/LC3I ratio and Beclin1 expression, but a dramatic reduction in the levels of p62 and pathway-related proteins (all P < 0.05). However, platelet activation and autophagy were aggravated by the Rapamycin treatment, and decreased following treatment with NAC, 3-MA, or NAC and 3-MA, together with increased activity of the PI3K/AKT/mTOR pathway. Additionally, decreased platelet activation and autophagy were observed in platelets treated with NAC and Rapamycin or Rapamycin and 3-MA compared with platelets treated with Rapamycin alone, suggesting that both NAC and 3-MA reversed the effects of Rapamycin. Conclusion: Inhibition of ROS production may reduce autophagy to suppress ox-LDL-induced platelet activation by activating PI3K/AKT/mTOR pathway.

Determinants of cardiac fibrosis in experimental hypermineralocorticoid states

1995 ◽  
Vol 269 (4) ◽  
pp. E657-E662 ◽  
Author(s):  
M. Young ◽  
G. Head ◽  
J. Funder
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Fibrosis ◽  
Cardiac Effect ◽  
Mineralocorticoid Receptor Antagonist ◽  
Salt Loading ◽  
Blood Pressure Elevation ◽  
Intracerebroventricular Infusion ◽  
Ru 28318 ◽  
Primary Action ◽  
Drinking Solution

Uninephrectomized rats maintained on 1.0% NaCl to drink and infused with aldosterone (0.75 microgram/h) for 8 wk have previously been shown to develop hypertension, cardiac hypertrophy, and cardiac fibrosis. In the present study we have shown that K+ supplementation (1.0% NaCl plus 0.4% KCl drinking solution) alters neither the interstitial nor the perivascular fibrotic response to mineralocorticoid treatment. Second, rats receiving 0.75 microgram/h 9 alpha-fluorocortisol, a mineralocorticoid and glucocorticoid agonist, respond with hypertension and cardiac fibrosis without cardiac hypertrophy. Finally, intracerebroventricular infusion of the mineralocorticoid receptor antagonist RU-28318 blocks blood pressure elevation, but not cardiac hypertrophy or fibrosis, when aldosterone is coinfused peripherally. We conclude that the myocardial fibrosis observed in response to chronic mineralocorticoid elevation and salt loading is a humorally mediated event independent of hypokalemia, hypertension, and cardiac hypertrophy. It remains to be determined whether the fibrosis observed in the presence of excess salt represents a direct (e.g., cardiac) effect of mineralocorticoid hormones or one mediated via a primary action on classical epithelial aldosterone target tissues (e.g., kidney).

scholarly journals Apocynum Tablet Protects against Cardiac Hypertrophy via Inhibiting AKT and ERK1/2 Phosphorylation after Pressure Overload

2014 ◽  
Vol 2014 ◽  
pp. 1-9
Author(s):  
Jianyong Qi ◽  
Qin Liu ◽  
Kaizheng Gong ◽  
Juan Yu ◽  
Lei Wang ◽  
...  
Keyword(s):  
Chinese Medicine ◽  
Cardiac Hypertrophy ◽  
Protein Expression ◽  
Molecular Mechanisms ◽  
Cardiac Fibrosis ◽  
Pressure Overload ◽  
Study Groups ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Cardioprotective Effects

Background. Cardiac hypertrophy occurs in many cardiovascular diseases. Apocynum tablet (AT), a traditional Chinese medicine, has been widely used in China to treat patients with hypertension. However, the underlying molecular mechanisms of AT on the hypertension-induced cardiac hypertrophy remain elusive. The current study evaluated the effect and mechanisms of AT on cardiac hypertrophy.Methods. We created a mouse model of cardiac hypertrophy by inducing pressure overload with surgery of transverse aortic constriction (TAC) and then explored the effect of AT on the development of cardiac hypertrophy using 46 mice in 4 study groups (combinations of AT and TAC). In addition, we evaluated the signaling pathway of phosphorylation of ERK1/2, AKT, and protein expression of GATA4 in the cardioprotective effects of AT using Western blot.Results. AT inhibited the phosphorylation of Thr202/Tyr204 sites of ERK1/2, Ser473 site of AKT, and protein expression of GATA4 and significantly inhibited cardiac hypertrophy and cardiac fibrosis at 2 weeks after TAC surgery (P<0.05).Conclusions. We experimentally demonstrated that AT inhibits cardiac hypertrophy via suppressing phosphorylation of ERK1/2 and AKT.

Fe–Cr/Al2O3 metal-ceramic composites: Nature and size of the metal particles formed during hydrogen reduction

1994 ◽  
Vol 9 (1) ◽  
pp. 229-235 ◽  
Author(s):  
Ch. Laurent ◽  
J.J. Demai ◽  
A. Rousset ◽  
K.R. Kannan ◽  
C.N.R. Rao
Keyword(s):  
Hydrogen Reduction ◽  
Ceramic Composites ◽  
X Ray Diffraction ◽  
X Ray ◽  
Total Reduction ◽  
Transmission Electron ◽  
Combined Use ◽  
Metal Ceramic ◽  
Different Temperatures ◽  
Metallic Species

Fe-Cr/Al2O3 metal-ceramic composites prepared by hydrogen reduction at different temperatures and for different periods have been investigated by a combined use of Mössbauer spectroscopy, x-ray diffraction, transmission electron microscopy, and energy-dispersive x-ray spectroscopy in order to obtain information on the nature of the metallic species formed. Total reduction of Fe3+ does not occur by increasing the reduction time at 1320 K from 1 to 30 h, and the amount of superparamagnetic metallic species is essentially constant (about 10%). Temperatures higher than 1470 K are needed to achieve nearly total reduction of substitutional Fe3+. Interestingly, iron favors the reduction of chromium. The composition of the Fe-Cr particles is strongly dependent on their size, the Cr content being higher in particles smaller than 10 nm.

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