scholarly journals PI3K as Mediator of Apoptosis and Contractile Dysfunction in TGFβ1-Stimulated Cardiomyocytes

Biology ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 670
Author(s):  
Paulin Brosinsky ◽  
Julia Bornbaum ◽  
Björn Warga ◽  
Lisa Schulz ◽  
Klaus-Dieter Schlüter ◽  
...  
Keyword(s):  
Contractile Function ◽  
Heart Function ◽  
Specific Inhibitor ◽  
Binding Activity ◽  
Pi3k Inhibitor ◽  
Contractile Dysfunction ◽  
Smad Signaling ◽  
Pi3k Inhibitor Ly294002 ◽  
Cell Shortening ◽  
Induced Apoptosis

Background: TGFβ1 is a growth factor that plays a major role in the remodeling process of the heart by inducing cardiomyocyte dysfunction and apoptosis, as well as fibrosis thereby restricting heart function. TGFβ1 mediates its effect via the TGFβ receptor I (ALK5) and the activation of SMAD transcription factors, but TGFβ1 is also known as activator of phosphoinositide-3-kinase (PI3K) via the non-SMAD signaling pathway. The aim of this study was to investigate whether PI3K is also involved in TGFβ1–induced cardiomyocytes apoptosis and contractile dysfunction. Methods and Results: Incubation of isolated ventricular cardiomyocytes with TGFβ1 resulted in impaired contractile function. Pre-incubation of cells with the PI3K inhibitor Ly294002 or the ALK5 inhibitor SB431542 attenuated the decreased cell shortening in TGFβ1–stimulated cells. Additionally, TGFβ-induced apoptosis was significantly reduced by the PI3K inhibitor Ly294002. Administration of a PI3Kγ-specific inhibitor AS605240 abolished the TGFβ effect on apoptosis and cell shortening. This was also confirmed in cardiomyocytes from PI3Kγ KO mice. Induction of SMAD binding activity and the TGFβ target gene collagen 1 could be blocked by the PI3K inhibitor Ly294002, but not by the specific PI3Kγ inhibitor AS605240. Conclusions: TGFβ1-induced SMAD activation, cardiomyocyte apoptosis, and impaired cell shortening are mediated via both, the ALK5 receptor and PI3K, in adult cardiomyocytes. PI3Kγ specifically contributes to apoptosis induction and impairment of contractile function independent of SMAD signaling.

scholarly journals The PI3K inhibitor LY294002 prevents p53 induction by DNA damage and attenuates chemotherapy-induced apoptosis

2005 ◽  
Vol 12 (12) ◽  
pp. 1578-1587 ◽  
Author(s):  
J Bar ◽  
N Lukaschuk ◽  
A Zalcenstein ◽  
S Wilder ◽  
R Seger ◽  
...  
Keyword(s):  
Dna Damage ◽  
Pi3k Inhibitor ◽  
Pi3k Inhibitor Ly294002 ◽  
Induced Apoptosis

Protection of capsaicin against hypoxia–reoxygenation-induced apoptosis of rat hippocampal neurons

2008 ◽  
Vol 86 (11) ◽  
pp. 785-792 ◽  
Author(s):  
Shi-Yin Guo ◽  
Guo-Ping Yang ◽  
De-Jian Jiang ◽  
Feng Wang ◽  
Tao Song ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Caspase 3 ◽  
Specific Inhibitor ◽  
Cell Number ◽  
Pyrrolidine Dithiocarbamate ◽  
Pi3k Inhibitor Ly294002 ◽  
Phosphoinositide 3 Kinase ◽  
Induced Apoptosis ◽  
Survival Effect ◽  
Hypoxia Reoxygenation

The aim of this study was to investigate the effect of capsaicin on hypoxia–reoxygenation (H/R)-induced apoptosis in primary rat hippocampal neurons. Three hours of hypoxia (1% O2) and subsequent reoxygenation for 24 h significantly increased the apoptotic death of hippocampal neurons, as evidenced by increases in both TUNEL-positive cell number and caspase-3 activity. Pretreatment with capsaicin (3–30 µmol/L) or the caspase-3-specific inhibitor acetyl-DEVD-CHO (100 µmol/L) markedly attenuated H/R-induced apoptosis in hippocampal neurons. Capsaicin also markedly induced the phosphorylation of Akt. The phosphoinositide 3-kinase (PI3K) inhibitor LY294002 (10 µmol/L) prevented any capsaicin-induced survival effect in hippocampal neurons. Intracellular levels of reactive oxygen species (ROS), which were greatly increased after H/R, were significantly inhibited by capsaicin, pyrrolidine dithiocarbamate (PDTC) (50 µmol/L), and LY294002. Taken together, these data suggest that capsaicin protects against H/R-induced apoptosis of hippocampal neurons via the PI3K/Akt-mediated signaling pathway, which is related to the inhibition of oxidative stress and caspase-3 activation.

scholarly journals The Synthetic Compound Norcantharidin Induced Apoptosis in Mantle Cell Lymphoma In Vivo and In Vitro through the PI3K-Akt-NF-κB Signaling Pathway

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Hongyan Lv ◽  
Yan Li ◽  
Hengfei Du ◽  
Jie Fang ◽  
Xiaoning Song ◽  
...  
Keyword(s):  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Signaling Pathway ◽  
Cell Lymphoma ◽  
Pi3k Inhibitor ◽  
Pi3k Inhibitor Ly294002 ◽  
Mantle Cell ◽  
Induced Apoptosis

This study aimed to elucidate the antitumor activity of norcantharidin (NCTD) against human mantle cell lymphoma (MCL). Cell proliferation and apoptosis were examined by MTS and flow cytometry. Caspase-3, -8, and -9 activities were detected with a colorimetric caspase protease assay. Apoptotic proteins—including PARP, cyclin D1, Bcl-2 family proteins, XIAP, and cIAP I—were studied by western blot. The phosphoinositide 3 kinase (PI3K) inhibitor LY294002 was used to investigate the involvement of the PI3K/Akt signaling pathway. In vivo studies were performed using Z138 cell xenografts in nude mice. NCTD inhibited proliferation and induced apoptosis of Z138 and Mino cells, both in vitro and in vivo. PI3Kp110αand p-Akt expressions were downregulated by NCTD treatment. NCTD downregulated NF-κB activity by preventing NF-κB phosphorylation and nuclear translocation. This effect was correlated with the suppression of NF-κB-regulated gene products, such as cyclin D1, BAX, survivin, Bcl-2, XIAP, and cIAP. This phenomenon was blocked by the PI3K inhibitor LY294002. Our results demonstrated that NCTD can induce growth arrest and apoptosis in MCL cells and that the mechanism may involve the PI3K/Akt/NF-κB signaling pathway. NCTD may have therapeutic and/or adjuvant therapeutic applications in the treatment of MCL.

PKC-mediated toxicity of elevated glucose concentration on cardiomyocyte function

2014 ◽  
Vol 307 (4) ◽  
pp. H587-H597 ◽  
Author(s):  
Mark W. Sims ◽  
James Winter ◽  
Sean Brennan ◽  
Robert I. Norman ◽  
G. André Ng ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Glucose Concentration ◽  
Contractile Function ◽  
Blood Glucose Concentration ◽  
Specific Inhibitor ◽  
Wistar Rat ◽  
Patch Clamp Recording ◽  
Electrical Stability ◽  
Extracellular Glucose Concentration ◽  
Extracellular Glucose

While it is well established that mortality risk after myocardial infarction (MI) increases in proportion to blood glucose concentration at the time of admission, it is unclear whether there is a direct, causal relationship. We investigated potential mechanisms by which increased blood glucose may exert cardiotoxicity. Using a Wistar rat or guinea-pig isolated cardiomyocyte model, we investigated the effects on cardiomyocyte function and electrical stability of alterations in extracellular glucose concentration. Contractile function studies using electric field stimulation (EFS), patch-clamp recording, and Ca2+ imaging were used to determine the effects of increased extracellular glucose concentration on cardiomyocyte function. Increasing glucose from 5 to 20 mM caused prolongation of the action potential and increased both basal Ca2+ and variability of the Ca2+ transient amplitude. Elevated extracellular glucose concentration also attenuated the protection afforded by ischemic preconditioning (IPC), as assessed using a simulated ischemia and reperfusion model. Inhibition of PKCα and β, using Gö6976 or specific inhibitor peptides, attenuated the detrimental effects of glucose and restored the cardioprotected phenotype to IPC cells. Increased glucose concentration did not attenuate the cardioprotective role of PKCε, but rather activation of PKCα and β masked its beneficial effect. Elevated extracellular glucose concentration exerts acute cardiotoxicity mediated via PKCα and β. Inhibition of these PKC isoenzymes abolishes the cardiotoxic effects and restores IPC-mediated cardioprotection. These data support a direct link between hyperglycemia and adverse outcome after MI. Cardiac-specific PKCα and β inhibition may be of clinical benefit in this setting.

scholarly journals Suppression of E1A-Mediated Transformation by the p50E4F Transcription Factor

1999 ◽  
Vol 19 (7) ◽  
pp. 4739-4749 ◽  
Author(s):  
Elma R. Fernandes ◽  
Robert J. Rooney
Keyword(s):  
Cell Death ◽  
Transcription Factor ◽  
Suppressive Effect ◽  
Culture Conditions ◽  
Binding Activity ◽  
Cellular Transcription Factor ◽  
Dna Binding Activity ◽  
3T3 Fibroblasts ◽  
Induced Apoptosis ◽  
Nih 3T3

ABSTRACT The adenovirus E1A gene can act as an oncogene or a tumor suppressor, with the latter effect generally arising from the induction of apoptosis or the repression of genes that provide oncogenic growth stimuli (e.g., HER-2/c-erbB2/neu) or increased metastatic invasiveness (e.g., metalloproteases). In this study, coexpression of E1A and p50E4F, a cellular transcription factor whose DNA binding activity is stimulated by E1A, suppressed colony formation by NIH 3T3 cells and transformation of primary rat embryo fibroblasts but had no observed effect in the absence of E1A. Domains in p50E4F required for stimulation of the adenovirus E4 promoter were required for the suppressive effect, indicating a transcriptional mechanism. In serum-containing media, retroviral expression of p50E4F in E1A13S/ras-transformed NIH 3T3 fibroblasts had little effect on subconfluent cultures but accelerated a decline in viability after the cultures reached confluence. Cell death occurred by both apoptosis and necrosis, with the predominance of each process determined by culture conditions. In serum-free media, p50E4F accelerated E1A-induced apoptosis. The results suggest that p50E4F sensitizes cells to signals or conditions that cause cell death.

Abstract 204: HAX-1: A Novel Regulator of Energetics and Oxidative Stress in the Heart

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Chi K Lam ◽  
Wen Zhao ◽  
Wenfeng Cai ◽  
Guansheng Liu ◽  
Phil Bidwell ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Heart Function ◽  
Ischemia Reperfusion ◽  
Calcium Handling ◽  
Calcium Kinetics ◽  
Atp Production ◽  
Homologous Protein ◽  
Induced Apoptosis ◽  
Factor C

Sarcoplasmic reticulum (SR) calcium handling is central not only in the control of heart function during excitation-contraction coupling but also in mitochondrial energetics and apoptosis. Recent studies have identified the anti-apoptotic protein, HS-1 associated protein X-1 (HAX-1) as a novel regulator of SR calcium cycling. Although HAX-1 has been shown to localize to mitochondria in various tissues, we found out that it also localizes to SR through its interaction with phospholamban (PLN) in cardiac muscle. Acute or chronic overexpression of HAX-1 in cardiomyocytes promoted PLN inhibition on the calcium ATPase (SERCA) and decreased cardiomyocyte calcium kinetics and contractile parameters. Accordingly, ablation of HAX-1 significantly enhanced SERCA activity and calcium kinetics. Furthermore, the HAX-1/PLN interaction appeared to also regulate cardiomyocyte survival. Indeed, overexpression of HAX-1 and the associated depressed SR Ca-load attenuated endoplasmic reticulum stress induced apoptosis, as evidenced by reduction of both caspase-12 activation and pro-apoptotic transcription factor C/EBP homologous protein induction during ischemia/reperfusion injury. In addition, the depressed SR Ca-cycling by HAX-1 overexpression was associated with reduced mitochondrial Ca-load as reflected by: a) hyper-phosphorylation of pyruvate dehydrogenase (PDH) and decreases in its activity, to diminish ATP production consistent with the attenuated energetic demand in these hearts; and b) reduced levels of reactive oxygen species, indicating protection from oxidative damage and preserved mitochondrial integrity. These findings suggest that HAX-1 is a key regulator of Ca-cycling, apoptosis and energetics in the heart. Thus, decreases in HAX-1 levels, observed during ischemia/reperfusion injury, may contribute to the deteriorated function and progression to heart failure development.

Abstract 331: Activation of the Safe Pathway Against Cardiac Ischemia-Reperfusion Injury Goes Beyond the Risk Pathway in the Late Pregnancy

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Jingyuan Li ◽  
Mansoureh Eghbali
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Late Pregnancy ◽  
Treated Group ◽  
Pi3k Inhibitor ◽  
Pi3k Inhibitor Ly294002 ◽  
Risk Pathway ◽  
Group 2 ◽  
Phosphoinositide 3 Kinase

Introduction: We have recently shown that the heart of late pregnant (LP) rodent is more prone to ischemia/reperfusion (I/R) injury compared to non-pregnant. We also reported that post-ischemic adminstartion of (ITLD) protects the LP hearts against I/R injury. Here we investigated Survivor Activating Factor Enhancement (SAFE) pathway, which requires the activation of the signal transducer and activator of transcription 3 (STAT-3) and it can successfully lessen cardiomyocyte death at the time of reperfusion, independently of the activation of the already well-described Reperfusion Injury Salvage Kinase (RISK) pathway (which includes activation of phosphoinositide 3-kinase (PI3K) signaling pathways) in ITLD-induced cardioprotetion. Methods: Isolated LP mouse hearts were subjected to 20 min ischemia followed by 40 reperfusion with 1) Krebs Henseleit buffer (CTRL group), 2) 1% intralipid (ITLD group) or 3) ITLD+STAT3 inhibitor Stattic (20 μM, Stattic group), and 4) ITLD+PI3K inhibitor LY294002 (45 μM). Hemodynamics and myocardial infarction were measured. Two-way and one-way ANOVA was used for statistical analysis. The data are from four to six mice in each group. P<0.05 was considered statistically significant. Values are expressed as mean± SE. Results: The Intralipid-induced cardioprotection was only partially abolished by PI3K inhibitor, LY294002, whereas it was fully abolished when stattic was applied at the end of 40 min reperfusion. The RPP was significantly lower in LY294002 treated group compared to the group treated with Intralipid alone, but still significantly higher than ITLD+Stattic: RPP=8881±1331 mmHg*beats/min in ITLD vs. 5212±1955 mmHg*beats/min in ITLD+LY, p<0.05; 1186±563 mmHg*beats/min in ITLD+Stattic vs. 5212±1955 mmHg*beats/min in ITLD+LY, p<0.05. The infarct size was also larger in LY294002 treated group when compared to Intralipid alone (32.8±3.1% in ITLD+LY vs. 21.7±2.6% in ITLD, p<0.05), but lower than ITLD+Stattic group (32.8±3.1% in ITLD+LY vs 47.9±2.5% ITLD+Stattic, p<0.05). Conclusion: Intralipid protects the heart of late pregnant mice against I/R injury mainly through SAFE-STAT3 pathway.

scholarly journals Dysfunction of muscle contraction with impaired intracellular Ca2+ handling in skeletal muscle and the effect of exercise training in male db/db mice

2019 ◽  
Vol 126 (1) ◽  
pp. 170-182 ◽  
Author(s):  
Hiroaki Eshima ◽  
Yoshifumi Tamura ◽  
Saori Kakehi ◽  
Kyoko Nakamura ◽  
Nagomi Kurebayashi ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Exercise Training ◽  
Muscle Contraction ◽  
Contractile Function ◽  
Contractile Force ◽  
Contractile Dysfunction ◽  
Muscle Contractile ◽  
Type 2 Diabetic

Type 2 diabetes is characterized by reduced contractile force production and increased fatigability of skeletal muscle. While the maintenance of Ca2+ homeostasis during muscle contraction is a requisite for optimal contractile function, the mechanisms underlying muscle contractile dysfunction in type 2 diabetes are unclear. Here, we investigated skeletal muscle contractile force and Ca2+ flux during contraction and pharmacological stimulation in type 2 diabetic model mice ( db/db mice). Furthermore, we investigated the effect of treadmill exercise training on muscle contractile function. In male db/db mice, muscle contractile force and peak Ca2+ levels were both lower during tetanic stimulation of the fast-twitch muscles, while Ca2+ accumulation was higher after stimulation compared with control mice. While 6 wk of exercise training did not improve glucose tolerance, exercise did improve muscle contractile dysfunction, peak Ca2+ levels, and Ca2+ accumulation following stimulation in male db/db mice. These data suggest that dysfunctional Ca2+ flux may contribute to skeletal muscle contractile dysfunction in type 2 diabetes and that exercise training may be a promising therapeutic approach for dysfunctional skeletal muscle contraction. NEW & NOTEWORTHY The purpose of this study was to examine muscle contractile function and Ca2+ regulation as well as the effect of exercise training in skeletal muscle in obese diabetic mice ( db/db). We observed impairment of muscle contractile force and Ca2+ regulation in a male type 2 diabetic animal model. These dysfunctions in muscle were improved by 6 wk of exercise training.

Losartan prevents contractile dysfunction in rat myocardium after left ventricular myocardial infarction

2001 ◽  
Vol 281 (5) ◽  
pp. H2150-H2158 ◽  
Author(s):  
Marcel C. G. Daniëls ◽  
Rebecca S. Keller ◽  
Pieter P. de Tombe
Keyword(s):  
Myocardial Infarction ◽  
Sarcomere Length ◽  
Contractile Function ◽  
Left Ventricular ◽  
Contractile Dysfunction ◽  
Treatment Results ◽  
Twitch Force ◽  
Rat Hearts ◽  
Myofilament Function ◽  
Active Peak

We studied the effects of chronic losartan (Los) treatment on contractile function of isolated right ventricular (RV) trabeculae from rat hearts 12 wk after left ventricular (LV) myocardial infarction (MI) had been induced by ligation of the left anterior descending artery at 4 wk of age. After recovery, one-half of the animals were started on Los treatment (MI+Los; 30 mg · kg−1 · day−1per os); the remaining animals were not treated (MI group). Rats without infarction or Los treatment served as controls (Con group). MI resulted in increases in LV and RV weight and unstressed LV cavity diameter; these were partially prevented by Los treatment. The active peak twitch force-sarcomere length relation was depressed in MI compared with either Con or MI+Los. Likewise, maximum Ca2+saturated twitch force was depressed in MI, whereas twitch relaxation and twitch duration were prolonged. Myofilament function, as measured in skinned trabeculae, was not significantly different among the Con, MI, and MI+Los groups. We conclude that Los prevents contractile dysfunction in rat RV trabeculae after LV MI. Our results suggest that the beneficiary effect of Los treatment results not from improved myofilament function but rather from improved myocyte Ca2+homeostasis.

Sign in / Sign up

Export Citation Format

Share Document