scholarly journals Astragaloside IV Protects Rat Cardiomyocytes from Hypoxia-Induced Injury by Down-Regulation of miR-23a and miR-92a

2018 ◽  
Vol 49 (6) ◽  
pp. 2240-2253 ◽  
Author(s):  
Licheng Gong ◽  
Hong Chang ◽  
Jingze Zhang ◽  
Gongliang Guo ◽  
Jingwei Shi ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Target Gene ◽  
Infarct Volume ◽  
Left Ventricular ◽  
Erk Signaling ◽  
Internal Diameter ◽  
H9c2 Cells ◽  
Astragaloside Iv ◽  
Down Regulation ◽  
Rat Cardiomyocytes

Background/Aims: Astragaloside IV (AS-IV), a traditional Chinese medicine isolated from Astragalus membranaceus, has been shown to exert cardioprotective effect previously. This study aimed to reveal the effects of AS-IV on hypoxia-injured cardiomyocyte. Methods: H9c2 cells were treated with various doses of AS-IV for 24 h upon hypoxia. CCK-8 assay, flow cytometry/Western blot, and qRT-PCR were respectively conducted to measure the changes in cell viability, apoptosis, and the expression of miR-23a and miR-92a. Sprague–Dawley rats were received coronary ligation, and were administrated by various doses of AS-IV for 14 days. The infarct volume and outcome of rats followed by ligation were tested by ultrasound, arteriopuncture and nitrotetrazolium blue chloride (NBT) staining. Results: We found that 10 μg/ml of AS-IV exerted myocardioprotective effects against hypoxia-induced cell damage, as AS-IV significantly increased H9c2 cells viability and decreased apoptosis. Interestingly, the myocardioprotective effects of AS-IV were alleviated by miR-23a and/or miR-92a overexpression. Knockdown of miR-23a and miR-92a activated PI3K/AKT and MAPK/ ERK signaling pathways. Bcl-2 was a target gene for miR-23a, and BCL2L2 was a target gene for miR-92a. In the animal model of myocardial infarction (MI), AS-IV significantly reduced the infarct volume, ejection fraction (EF), shortening fraction (FS) and LV systolic pressure (LVSP), and significantly increased left ventricular end-diastolic internal diameter (LVEDd). And also, the elevated expression of miR-23a and miR-92a in MI rat was reduced by AS-IV. Conclusion: AS-IV protected cardiomyocytes against hypoxia-induced injury possibly via down-regulation of miR-23a and miR-92a, and via activation of PI3K/AKT and MAPK/ERK signaling pathways.

GPER mediates estrogen cardioprotection against epinephrine-induced stress

2021 ◽  
Author(s):  
Lu Fu ◽  
Hongyuan Zhang ◽  
Jeremiah Ong’achwa Machuki ◽  
Tingting Zhang ◽  
Lin Han ◽  
...  
Keyword(s):  
Culture Supernatant ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Protective Role ◽  
Left Ventricular ◽  
Internal Diameter ◽  
High Dose ◽  
Adult Rats ◽  
Rat Cardiomyocytes ◽  
Lactate Dehydrogenase Release

Currently, there are no conventional treatments for stress-induced cardiomyopathy (SCM, also known as Takotsubo syndrome), and the existing therapies are not effective. The recently discovered G protein- coupled estrogen receptor (GPER) executes the rapid effects of estrogen (E2). In this study, we investigated the effects and mechanism of GPER on epinephrine (Epi)-induced cardiac stress. SCM was developed with a high dose of Epi in adult rats and human-induced pluripotent stem cells–derived cardiomyocytes(hiPSC-CMs). (1) GPER activation with agonist G1/ E2 prevented an increase in left ventricular internal diameter at end-systole, the decrease both in ejection fraction and cardiomyocyte shortening amplitude elicited by Epi. (2) G1/ E2 mitigated heart injury induced by Epi, as revealed by reduced plasma brain natriuretic peptide and lactate dehydrogenase release into culture supernatant. (3) G1/E2 prevented the raised phosphorylation and internalization of β2-adrenergic receptors（β2AR）. (4) Blocking Gαi abolished the cardiomyocyte contractile inhibition by Epi. G1/E2 downregulated Gαi activity of cardiomyocytes and further upregulated cyclic adenosine monophosphate concentration in culture supernatant treated with Epi. (5) G1/E2 rescued decreased Ca2+ amplitude and Ca2+ channel current (ICa-L) in rat cardiomyocytes. Notably, the above effects of E2 were blocked by the GPER antagonist, G15. In hiPSC-CM (which expressed GPER, β1AR and β2ARs), knockdown of GPER by siRNA abolished E2 effects on increasing ICa-L and action potential duration in the stress state. In conclusion, GPER played a protective role against SCM. Mechanistically, this effect was mediated by balancing the coupling of β2AR to the Gαs and Gαi signalling pathways.

scholarly journals MicroRNA-145 Aggravates Hypoxia-Induced Injury by Targeting Rac1 in H9c2 Cells

2017 ◽  
Vol 43 (5) ◽  
pp. 1974-1986 ◽  
Author(s):  
Ximing Wang ◽  
Yanxia Zhang ◽  
Hongshan Wang ◽  
Genshang Zhao ◽  
Xianen Fa
Keyword(s):  
Target Gene ◽  
Target Genes ◽  
Underlying Mechanism ◽  
Mitogen Activated Protein Kinase ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
H9c2 Cells ◽  
Down Regulation ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

Background/Aims: Myocardial infarction (MI) is a leading cause of morbidity and mortality. Here, we sought to explore the potential role and underlying mechanism of miR-145 in MI. Methods: H9c2 cells were cultured under persistent hypoxia to simulate MI. The hypoxia-induced injury was assessed on the basis of cell viability, migration, invasion and apoptosis. The expression of miR-145 was evaluated by qRT-PCR and the influence of aberrantly expressed miR-145 on H9c2 cells under hypoxia was also estimated. Utilizing bioinformatics methods, the target genes of miR-145 were verified by luciferase reporter assay. Then, effects of abnormally expressed target gene on miR-145 silenced H9c2 cells were assessed. Finally, the phosphorylation levels of key kinases in the phosphatidylinositol-3-kinase (PI3K)/AKT and the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathways were detected by Western blot analysis. Results: Hypoxia remarkably lowered viability, migration and invasion but promoted cell apoptosis. Meantime, the miR-145 level was up-regulated in H9c2 cells under hypoxia. Following experiments suggested that hypoxia-induced injury was exacerbated by miR-145 overexpression while was alleviated by miR-145 silence. Rac1 was predicted and further validated to be a target gene of miR-145. The influence of miR-145 silencing on H9c2 cells under hypoxia could be reversed by down-regulation of Rac1. Additionally, the phosphorylation levels of PI3K, AKT, MAPK and ERK were all elevated in miR-145 silenced cells and these alterations were reversed by down-regulation of Rac1. Conclusion: miR-145 silencing could protect H9c2 cells against hypoxia-induced injury by targeting Rac1, in which PI3K/AKT and MAPK/ERK pathways might be involved.

scholarly journals L-Carnitine: An Antioxidant Remedy for the Survival of Cardiomyocytes under Hyperglycemic Condition

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Fernanda Vacante ◽  
Pamela Senesi ◽  
Anna Montesano ◽  
Alice Frigerio ◽  
Livio Luzi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dysfunction ◽  
Signaling Pathways ◽  
Stress Condition ◽  
Cardiac Cells ◽  
Ros Production ◽  
Protective Effects ◽  
H9c2 Cells ◽  
Rat Cardiomyocytes ◽  
Oxidative Stress Condition

Background. Metabolic alterations as hyperglycemia and inflammation induce myocardial molecular events enhancing oxidative stress and mitochondrial dysfunction. Those alterations are responsible for a progressive loss of cardiomyocytes, cardiac stem cells, and consequent cardiovascular complications. Currently, there are no effective pharmacological measures to protect the heart from these metabolic modifications, and the development of new therapeutic approaches, focused on improvement of the oxidative stress condition, is pivotal. The protective effects of levocarnitine (LC) in patients with ischemic heart disease are related to the attenuation of oxidative stress, but LC mechanisms have yet to be fully understood. Objective. The aim of this work was to investigate LC’s role in oxidative stress condition, on ROS production and mitochondrial detoxifying function in H9c2 rat cardiomyocytes during hyperglycemia. Methods. H9c2 cells in the hyperglycemic state (25 mmol/L glucose) were exposed to 0.5 or 5 mM LC for 48 and 72 h: LC effects on signaling pathways involved in oxidative stress condition were studied by Western blot and immunofluorescence analysis. To evaluate ROS production, H9c2 cells were exposed to H2O2 after LC pretreatment. Results. Our in vitro study indicates how LC supplementation might protect cardiomyocytes from oxidative stress-related damage, preventing ROS formation and activating antioxidant signaling pathways in hyperglycemic conditions. In particular, LC promotes STAT3 activation and significantly increases the expression of antioxidant protein SOD2. Hyperglycemic cardiac cells are characterized by impairment in mitochondrial dysfunction and the CaMKII signal: LC promotes CaMKII expression and activation and enhancement of AMPK protein synthesis. Our results suggest that LC might ameliorate metabolic aspects of hyperglycemic cardiac cells. Finally, LC doses herein used did not modify H9c2 growth rate and viability. Conclusions. Our novel study demonstrates that LC improves the microenvironment damaged by oxidative stress (induced by hyperglycemia), thus proposing this nutraceutical compound as an adjuvant in diabetic cardiac regenerative medicine.

P4461Chronic administration of Empagliflozin induces cardioprotection in vivo in absence of diabetes mellitus

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
F Abu Qourah ◽  
P E Nikolaou ◽  
S Femmino ◽  
M Tsoumani ◽  
A Varela ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Blood Pressure ◽  
Body Weight ◽  
Infarct Size ◽  
Signaling Pathways ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Myocardial Infarct Size ◽  
H9c2 Cells ◽  
Glucose Levels

Abstract Background/Introduction We have recently shown that empagliflozin (EMPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor approved for type 2 diabetes mellitus management reduces myocardial infarct size in diabetic mice undergone ischemia/reperfusion (I/R) after chronic administration. However its effect on non-diabetic myocardium remains unspecified. Purpose We aimed to investigate: (i) the effect of EMPA on myocardial function and infarct size after I/R in healthy mice, in the absence of diabetes mellitus, (ii) the underlying signaling pathways, (iii) its effects on cell survival in rat embryonic-heart-derived cardiomyoblasts (H9C2) treated with the inhibitor of STAT3, STATTIC. Methods C57BL/6 mice were initially randomized into two groups, Control and EMPA (n=7 per group) and treated with 5% DMSO in water for injection and EMPA at a dose of 10mg/kg/day with 5% DMSO in water for injection, respectively, for 6 weeks. After this period, the mice were subjected to 30 minutes of I and 2 hours of R and infarct size was evaluated. Body weight, blood pressure, blood glucose levels and left ventricular shortening measurements by echocardiography, were taken at baseline and at the end of the treatment. Furthermore, in order to assess potential differences in the signaling cascades involved at different time points of reperfusion, additional mice were randomized into Control and EMPA groups which were furtherly subdivided into groups (n=4) of 10' and (n=4) of 120' of reperfusion each. The mice were subjected to I/R and myocardial biopsies were obtained for the assessment of the signaling cascade at the 10th and 120th minutes of reperfusion. H9C2 cells subjected to ischemia–reoxygenation were treated with STATIC (0.5, 1, and 10 μM) during the 3 hours of reoxygenation and evaluated for viability. Results Body weight, blood pressure and glucose levels remained unchanged between the groups. We observed no statistically significant change in left ventricular fractional shortening in both groups at baseline (41.0% ± 1.92 vs 40.5% ± 2.7) and after the end of the 6th week (42.7% ± 2.8 vs 40.9% ± 4.1). Infarct size was significantly reduced in EMPA group compared to the Control one (29.5% ± 3.0 vs 45.8% ± 3.2, p<0.05). Phosphorylation of STAT3 was significantly increased at the 10th minute of reperfusion but remained unchanged at the 120th compared to control. The contribution of STAT3 in EMPA-mediated effects was evaluated in H9C2 cells using different doses of STATIC; our results indicate that EMPA completely lost its activity when STAT3 is inhibited. However STATIC per se induces cell death even at low doses. Conclusion(s) EMPA reduces infarct size in healthy mice indicating that its cardioprotective effect is independent of the presence of diabetes mellitus. STAT3 activation can be considered as a cardioprotective mechanism of EMPA, however other signaling pathways could be involved in EMPA mechanism of action and are currently under investigation.

scholarly journals Zi Shen Huo Luo Formula Prevents Aldosterone-Induced Cardiomyocyte Hypertrophy and Cardiac Fibroblast Proliferation by Regulating the Striatin-Mediated MR/EGFR/ERK Signaling Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Weike Feng ◽  
Yue Zhao ◽  
Xiaotong Song ◽  
Yuan Wang ◽  
Qian Chen ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Cardiac Fibroblasts ◽  
Animal Experiments ◽  
Left Ventricular ◽  
Erk Signaling ◽  
Cardiomyocyte Hypertrophy ◽  
Membrane Localization ◽  
Myocardial Remodeling ◽  
Rat Cardiomyocytes

Inappropriate activation of the renin-angiotensin-aldosterone system (RAAS) is an important factor in the development of hypertension. Excessive aldosterone can lead to myocardial extracellular matrix collagen proliferation, fibrosis, and cardiomyocyte hypertrophy and aggravate maladaptive remodeling. The results of our previous clinical and animal experiments suggested that Zi Shen Huo Luo Formula (ZSHLF) combined with perindopril can effectively control the process of left ventricular hypertrophy (LVH). The purpose of this study was to investigate whether ZSHLF-treated serum inhibits the membrane localization of the striatin-mediated mineralocorticoid receptor (MR) and affects MR-mediated nongenomic effects and the downstream epidermal growth factor receptor (EGFR)/extracellular regulated kinase (ERK) signaling pathways, thereby improving aldosterone-induced myocardial remodeling. Serum containing ZSHLF was prepared and used to treat rat cardiomyocytes and cardiac fibroblasts in vitro after aldosterone induction and striatin knockdown by small interfering RNA (siRNA). Cell-based assays were carried out to determine the cardiomyocyte surface area and assess the proliferation rate and hydroxyproline secretion of cardiac fibroblasts. Quantitative real-time PCR (qRT-PCR), immunoprecipitation (IP), and Western blotting were performed to evaluate the striatin-mediated MR/EGFR/ERK signaling pathway. In the present study, ZSHLF attenuated the aldosterone-induced hypertrophy of cardiomyocytes and inhibited the proliferation and collagen synthesis of cardiac fibroblasts. ZSHLF also reduced striatin mRNA expression and inhibited striatin and MR binding, membrane MR protein expression, and EGFR and ERK1/2 phosphorylation. Furthermore, after striatin silencing with siRNA, some of the effects of ZSHLF were not changed significantly. In conclusion, ZSHLF inhibits the downstream EGFR/ERK signaling pathway by blocking the striatin-mediated membrane localization of MR, which may be an important molecular mechanism by which ZSHLF improves aldosterone-induced myocardial remodeling.

The Impact of Royal Jelly against Hepatic Ischemia/Reperfusion-Induced Hepatocyte Damage in Rats: The Role of Cytoglobin, Nrf-2/HO-1/COX-4, and P38-MAPK/NF-κB-p65/TNF-α Signaling Pathways

2020 ◽  
Vol 14 (1) ◽  
pp. 88-100
Author(s):  
Fares E.M. Ali ◽  
Heba M. Saad Eldien ◽  
Nashwa A.M. Mostafa ◽  
Abdulrahman H. Almaeen ◽  
Mohamed R.A. Marzouk ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
P38 Mapk ◽  
Royal Jelly ◽  
Ischemia Reperfusion ◽  
Histopathological Changes ◽  
Down Regulation ◽  
Hepatic Ischemia ◽  
Tnf Α ◽  
Hepatic Ischemia Reperfusion ◽  
The Impact

Objective: The present study was conducted to elucidate the underlying molecular mechanism as well as the potential hepatoprotective effects of royal jelly (RJ) against hepatic ischemia/reperfusion (IR) injury. Methods: Rats were assigned into four groups; sham (received vehicle), IR (30 minutes ischemia and 45 minutes reperfusion), sham pretreated with RJ (200 mg/kg P.O.), and IR pretreated with RJ (200 mg/kg P.O.). The experiment has lasted for 28 days. Results: Hepatic IR significantly induced hepatic dysfunctions, as manifested by elevation of serum transaminases, ALP and LDH levels. Moreover, hepatic IR caused a significant up-regulation of P38-MAPK, NF-κB-p65, TNF-α and MDA levels along with marked down-regulation of Nrf-2, HO-1, COX-4, cytoglobin, IκBa, IL-10, GSH, GST and SOD levels. Additionally, marked histopathological changes were observed after hepatic IR injury. On the contrary, pretreatment with RJ significantly improved hepatic functions along with the alleviation of histopathological changes. Moreover, RJ restored oxidant/antioxidant balance as well as hepatic expressions of Nrf-2, HO-1, COX-4, and cytoglobin. Simultaneously, RJ significantly mitigated the inflammatory response by down-regulation of P38-MAPK, NF-κB-p65, TNF-α expression. Conclusion: The present results revealed that RJ has successfully protected the liver against hepatic IR injury through modulation of cytoglobin, Nrf-2/HO-1/COX-4, and P38-MAPK/NF-κB-p65/TNF-α signaling pathways.

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