scholarly journals miR-155-5p upregulation ameliorates myocardial insulin resistance via mTOR signaling in chronic alcohol drinking rats

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e10920
Author(s):  
Zhaoping Li ◽  
Zhenzhen Hu ◽  
Yan Meng ◽  
Hongzhao Xu ◽  
Yali Wei ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cardiac Function ◽  
Insulin Receptor ◽  
Alcohol Drinking ◽  
Cardiac Dysfunction ◽  
Alcohol Intake ◽  
Mtor Signaling ◽  
Chronic Alcohol ◽  
Mtor Signaling Pathway ◽  
Myocardial Insulin Resistance

Background Chronic alcohol intake is associated with an increased risk of alcoholic cardiomyopathy, which may present with pathological changes such as myocardial insulin resistance, leading to ventricular dilation and cardiac dysfunction. Although a correlation between microRNA-155 (miR-155) and insulin signaling has been identified, the underlying mechanism has not been elucidated to date. The purpose of the study was to determine whether overexpression of miR-155-5p in vivo could ameliorate chronic alcohol-induced myocardial insulin resistance and cardiac dysfunction. Material and Methods Wistar rats were fed with either alcohol or water for 20 weeks to establish chronic alcohol intakes model. Then the alcohol group were divided into three groups: model group, miRNA-155 group and AAV-NC group. Rats undergoing alcohol treatment were injected with AAV-miRNA-155 (adeno-associated virus 9) or its negative control AAV-NC, respectively. Gene expression was determined by real-time PCR, and protein expression was determined by western blot. Echocardiography was performed to assess terminal cardiac function. Insulin responsiveness was determined through the quantification of phosphorylated insulin receptor substrate 1 (ser 307) and phosphorylated insulin receptor (Tyr 1185) levels. Results We found that cardiac function was attenuated in chronic alcohol intake rats, with an activated mammalian target of rapamycin (mTOR) signaling pathway, accompanied by an increase in p-IRS1(ser 307) and a decrease in p-IR (Tyr 1185) level in myocardial tissue. Also, alcohol drinking significantly up-regulated miR-155-5p level and its overexpression decreased p-IRS1 (ser 307) and increased p-IR (Tyr 1185) levels, and meanwhile inhibited the mTOR signaling pathway. Conclusion miR-155-5p upregulation ameliorates myocardial insulin resistance via the mTOR signaling in chronic alcohol drinking rats. We propose that miR-155 may serve as a novel potential therapeutic target for alcoholic heart disease.

Akt is a critical node of acute myocardial insulin resistance and cardiac dysfunction after cardiopulmonary bypass

Life Sciences ◽  
2019 ◽  
Vol 234 ◽  
pp. 116734 ◽  
Author(s):  
Zhifa Wang ◽  
Yunya Wang ◽  
Yuehu Han ◽  
Qiang Yin ◽  
Sheng Hu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cardiopulmonary Bypass ◽  
Cardiac Dysfunction ◽  
Critical Node ◽  
Myocardial Insulin Resistance

scholarly journals Targeting mir128-3p alleviates myocardial insulin resistance and prevents ischemia-induced heart failure

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Andrea Ruiz-Velasco ◽  
Min Zi ◽  
Susanne S Hille ◽  
Tayyiba Azam ◽  
Namrita Kaur ◽  
...  
Keyword(s):  
Heart Failure ◽  
Insulin Resistance ◽  
Cardiac Dysfunction ◽  
Cardiac Injury ◽  
Induced Pluripotent Stem Cell ◽  
Mitogen Activated Protein Kinase ◽  
Rat Cardiomyocytes ◽  
Functional Studies ◽  
Mitogen Activated Protein ◽  
Myocardial Insulin Resistance

Myocardial insulin resistance contributes to heart failure in response to pathological stresses, therefore, a therapeutic strategy to maintain cardiac insulin pathways requires further investigation. We demonstrated that insulin receptor substrate 1 (IRS1) was reduced in failing mouse hearts post-myocardial infarction (MI) and failing human hearts. The mice manifesting severe cardiac dysfunction post-MI displayed elevated mir128-3p in the myocardium. Ischemia-upregulated mir128-3p promoted Irs1 degradation. Using rat cardiomyocytes and human-induced pluripotent stem cell-derived cardiomyocytes, we elucidated that mitogen-activated protein kinase 7 (MAPK7, also known as ERK5)-mediated CCAAT/enhancer-binding protein beta (CEBPβ) transcriptionally represses mir128-3p under hypoxia. Therapeutically, functional studies demonstrated gene therapy-delivered cardiac-specific MAPK7 restoration or overexpression of CEBPβ impeded cardiac injury after MI, at least partly due to normalization of mir128-3p. Furthermore, inhibition of mir128-3p preserved Irs1 and ameliorated cardiac dysfunction post-MI. In conclusion, we reveal that targeting mir128-3p mitigates myocardial insulin resistance, thereafter slowing down the progression of heart failure post-ischemia.

scholarly journals Galangin and Pinocembrin from Propolis Ameliorate Insulin Resistance in HepG2 Cells via Regulating Akt/mTOR Signaling

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Yinkang Liu ◽  
Xiali Liang ◽  
Gensheng Zhang ◽  
Lingjie Kong ◽  
Wenjun Peng ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Pyruvate Kinase ◽  
Glycogen Content ◽  
Critical Role ◽  
Glucose Consumption ◽  
Mtor Signaling ◽  
Compelling Evidence ◽  
Mtor Signaling Pathway ◽  
Ameliorate Insulin Resistance

Insulin resistance has a critical role in type 2 diabetes. The aim of this study was to investigate the effect of pinobanksin, galangin, chrysin, and pinocembrin from propolis on insulin resistance. Our study shows that galangin and pinocembrin can ameliorate insulin resistance; on the contrary, pinobanksin and chrysin are ineffective. Galangin and pinocembrin treatments substantially increase glucose consumption and glycogen content by enhancing the activities of hexokinase and pyruvate kinase. Galangin treatment with 80 μM increased hexokinase and pyruvate kinase activities by 21.94% and 29.12%, respectively. Moreover, we hypothesize that galangin and pinocembrin may have a synergistic effect on the improvement of insulin resistance via Akt/mTOR signaling pathway, through distinctly upregulating the phosphorylation of IR, Akt, and GSK3β and remarkably downregulating the phosphorylation of IRS. Most notably, this is the first study to our knowledge to investigate pinocembrin about the alleviation of insulin resistance. Our results provide compelling evidence for the depth development of propolis products to ameliorate insulin resistance.

Vitamin D Deficiency in Rats Causes Cardiac Dysfunction by Inducing Myocardial Insulin Resistance

2019 ◽  
Vol 63 (17) ◽  
pp. 1900109 ◽  
Author(s):  
Hina Lateef Nizami ◽  
Parmeshwar Katare ◽  
Pankaj Prabhakar ◽  
Yashwant Kumar ◽  
Sudheer Kumar Arava ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Vitamin D ◽  
Vitamin D Deficiency ◽  
Cardiac Dysfunction ◽  
Myocardial Insulin Resistance

scholarly journals Protective Effect of Tomato-Oleoresin Supplementation on Oxidative Injury Recoveries Cardiac Function by Improving β-Adrenergic Response in a Diet-Obesity Induced Model

Antioxidants ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 368
Author(s):  
Artur Junio Togneri Ferron ◽  
Giancarlo Aldini ◽  
Fabiane Valentini Francisqueti-Ferron ◽  
Carol Cristina Vágula de Almeida Silva ◽  
Silmeia Garcia Zanati Bazan ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Oxidative Damage ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Control Diet ◽  
Adrenergic Response ◽  
Diet Control ◽  
To Receive

The system redox imbalance is one of the pathways related to obesity-related cardiac dysfunction. Lycopene is considered one of the best antioxidants. The aim of this study was to test if the tomato-oleoresin would be able to recovery cardiac function by improving β-adrenergic response due its antioxidant effect. A total of 40 animals were randomly divided into two experimental groups to receive either the control diet (Control, n = 20) or a high sugar-fat diet (HSF, n = 20) for 20 weeks. Once cardiac dysfunction was detected by echocardiogram in the HSF group, animals were re- divided to begin the treatment with Tomato-oleoresin or vehicle, performing four groups: Control (n = 6); (Control + Ly, n = 6); HSF (n = 6) and (HSF + Ly, n = 6). Tomato oleoresin (10 mg lycopene/kg body weight (BW) per day) was given orally every morning for a 10-week period. The analysis included nutritional and plasma biochemical parameters, systolic blood pressure, oxidative parameters in plasma, heart, and cardiac analyses in vivo and in vitro. A comparison among the groups was performed by two-way analysis of variance (ANOVA). Results: The HSF diet was able to induce obesity, insulin-resistance, cardiac dysfunction, and oxidative damage. However, the tomato-oleoresin supplementation improved insulin-resistance, cardiac remodeling, and dysfunction by improving the β-adrenergic response. It is possible to conclude that tomato-oleoresin is able to reduce the oxidative damage by improving the system’s β-adrenergic response, thus recovering cardiac function.

scholarly journals Sodium–Glucose CoTransporter-2 Inhibitor Empagliflozin Ameliorates Sunitinib-Induced Cardiac Dysfunction via Regulation of AMPK–mTOR Signaling Pathway–Mediated Autophagy

2021 ◽  
Vol 12 ◽  
Author(s):  
Changzhen Ren ◽  
Kaiqiang Sun ◽  
Yanda Zhang ◽  
Yangxi Hu ◽  
Bowen Hu ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Signaling Pathway ◽  
Cardiac Dysfunction ◽  
Sglt2 Inhibitor ◽  
Left Ventricular ◽  
Sglt2 Inhibitors ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Sodium Glucose Cotransporter ◽  
H9c2 Cardiomyocytes

Background: Sodium–glucose cotransporter-2 (SGLT2) inhibitors have been shown to decrease the adverse cardiac events and risks of cardiovascular mortality among patients with or without diabetes, which has made these drugs promising treatment options for patients with chronic heart failure. Cardiac dysfunction is a common and severe side effect induced by cancer chemotherapies, which seriously affects the prognosis and life quality of tumor patients. However, it is not clear whether SGLT2 inhibitors have cardiovascular benefits in patients with cancer chemotherapy–related cardiac dysfunction. We aimed to determine whether empagliflozin (EMPA), an SGLT2 inhibitor, has a protective role against sunitinib (SNT)-induced cardiac dysfunction in a mouse model.Methods: Male C57BL/6J mice were randomized into control (control, n = 8), empagliflozin (EMPA, n = 8), sunitinib (SNT, n = 12), or sunitinib and empagliflozin coadministration (SNT + EMPA, n = 12) groups. EMPA, SNT, or SNT-combined EMPA was given via oral gavage for consecutive 28 days. Cardiovascular functions and pathological changes were examined, and the underlying mechanisms of EMPA’s effects were investigated in H9c2 cardiomyocytes.Results: Mice in the SNT group exhibited dramatically elevated blood pressure (systolic blood pressure [SBP] 134.30 ± 6.455 mmHg vs. 114.85 ± 6.30 mmHg) and impaired left ventricular function (left ventricular ejection fraction [LVEF] 50.24 ± 3.06% vs. 84.92 ± 2.02%), as compared with those of the control group. However, EMPA could ameliorate SNT-induced cardiotoxicity, both in terms of SBP (117.51 ± 5.28 mmHg vs. 134.30 ± 6.455 mmHg) and LVEF (76.18 ± 5.16% vs. 50.24 ± 3.06 %). In H9c2 cardiomyocytes, SNT-induced cardiomyocyte death and cell viability loss as well as dysfunction of adenosine 5’-monophosphate–activated protein kinase–mammalian target of rapamycin (AMPK-mTOR) signaling–mediated autophagy were restored by EMPA. However, these favorable effects mediated by EMPA were blocked by the inhibition of AMPK or autophagy.Conclusion: EMPA could ameliorate SNT-induced cardiac dysfunction via regulating cardiomyocyte autophagy, which was mediated by the AMPK-mTOR signaling pathway. These findings supported that SGLT2 inhibitor therapy could be a potential cardioprotective approach for cardiovascular complications among patients receiving SNT. However, these favorable effects still need to be validated in clinical trials.

Mammalian Target of Rapamycin Is Activated in Association with Myometrial Proliferation during Pregnancy

Endocrinology ◽  
2009 ◽  
Vol 150 (10) ◽  
pp. 4672-4680 ◽  
Author(s):  
Shabana Jaffer ◽  
Oksana Shynlova ◽  
Stephen Lye
Keyword(s):  
Insulin Receptor ◽  
Signaling Pathway ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Mtor Signaling ◽  
Target Of Rapamycin ◽  
Insulin Receptor Substrate ◽  
Mtor Signaling Pathway ◽  
Insulin Receptor Substrate 1 ◽  
Ovx Rats

Abstract The adaptive growth of the uterus during gestation involves gradual changes in cellular phenotypes from the early proliferative to the intermediate synthetic phase of cellular hypertrophy, ending in the final contractile/labour phenotype. The mammalian target of rapamycin (mTOR) signaling pathway regulates cell growth and proliferation in many tissues. We hypothesized that mTOR was a mediator of hormone-initiated myometrial hyperplasia during gestation. The protein expression and phosphorylation levels of mTOR, its upstream regulators [insulin receptor substrate-1, phosphoinositide-3-kinase (PI3K), Akt], and downstream effectors [S6-kinase-1 (S6K1) and eI4FE-binding protein 1 (4EBP1)] were analyzed throughout normal pregnancy in rats. In addition, we used an ovariectomized (OVX) rat model to analyze the modulation of the mTOR pathway and proliferative activity of the uterine myocytes by estradiol alone and in combination with the mTOR-specific inhibitor rapamycin. Our results demonstrate that insulin receptor substrate-1 protein levels and the phosphorylated (activated) forms of PI3K, mTOR, and S6K1 were significantly up-regulated in the rat myometrium during the proliferative phase of pregnancy. Treatment of the OVX rats with estradiol caused a transient increase in IGF-I followed by an up-regulation of the PI3K/mTOR pathway, which became apparent by a cascade of phosphorylation reactions (P-P85, P-Akt, P-mTOR, P-S6K1, and P-4EBP1). Rapamycin blocked activation of P-mTOR, P-S6K1, and P-4EBP1 proteins and significantly reduced the number of proliferating cells in the myometrium of OVX rats. Our in vivo data demonstrate that estradiol was able to activate the PI3K/mTOR signaling pathway in uterine myocytes and suggest that this activation is responsible for the induction of myometrial hyperplasia during early gestation.

Chronic Alcohol Intake Exacerbates Cardiac Dysfunction After Myocardial Infarction

2020 ◽  
Vol 55 (5) ◽  
pp. 524-530
Author(s):  
Yu Liang ◽  
Xuewen Xu ◽  
Qin Li ◽  
Yan Deng ◽  
Maodi Xie ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Drinking Water ◽  
Mitochondrial Function ◽  
Cardiac Dysfunction ◽  
Alcohol Intake ◽  
Alcohol Exposure ◽  
Heart Weight ◽  
Vehicle Group ◽  
Coronary Artery Ligation ◽  
Chronic Alcohol

Abstract Aims Alcohol intake is a risk factor for cardiovascular diseases. This study was designed to investigate whether chronic alcohol intake affects myocardial infarction (MI)-induced cardiac remodeling and heart failure. Methods Eight-week-old male C57BL/6 mice were randomly divided into four groups: Sham group (Sham), MI plus drinking water group (MI + Vehicle), and MI plus daily alcohol intake for 6 weeks with or without gavage of additional alcohol every 3 days (MI + Alcohol and MI + Alcohol + G). The MI were induced by permanent left anterior descending (LAD) coronary artery ligation surgery before vehicle or alcohol treatment. The blood alcohol concentration (BAC), cardiac function, release of cardiac enzymes, pathological changes and mitochondrial function were measured. Results As expected, supplementation of alcohol in drinking water significantly increased random BAC in mice. Long-term exposure to alcohol further reduced body weight, ejection fraction and fractional shortening in comparison with the MI + Vehicle group. Histopathological data showed that alcohol increased fibrosis in infarct zone, which was well correlated with the functional decline. Also, as compared to the MI + Vehicle group, the adenosine diphosphate-supported respiratory function of freshly isolated cardiac mitochondria was inhibited in the MI + Alcohol + G group. Besides, upon MI-induced cardiac damage, we did not observe further changes in heart weight, cardiomyocyte enlargement in remote zone, exercise capacity, lung edema and the release of cardiac enzyme after chronic alcohol intake. Conclusions Our study demonstrated that chronic daily alcohol exposure exacerbated MI-induced cardiac dysfunction, which is related to promoted myocardial fibrosis and inhibited mitochondrial function.

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