scholarly journals Inhibition of calpain reduces cell apoptosis by suppressing mitochondrial fission in acute viral myocarditis

2021 ◽  
Author(s):  
Hui Shi ◽  
Ying Yu ◽  
Xiaoxiao Liu ◽  
Yong Yu ◽  
Minghui Li ◽  
...  
Keyword(s):  
Western Blotting ◽  
Mitochondrial Function ◽  
Mitochondrial Fission ◽  
Viral Myocarditis ◽  
Cardiomyocyte Apoptosis ◽  
Neonatal Rat ◽  
Tunel Staining ◽  
Mitochondrial Morphology ◽  
Rat Cardiomyocytes ◽  
Cvb3 Infection

AbstractCardiomyocyte apoptosis is critical for the development of viral myocarditis (VMC), which is one of the leading causes of cardiac sudden death in young adults. Our previous studies have demonstrated that elevated calpain activity is involved in the pathogenesis of VMC. This study aimed to further explore the underlying mechanisms. Neonatal rat cardiomyocytes (NRCMs) and transgenic mice overexpressing calpastatin were infected with coxsackievirus B3 (CVB3) to establish a VMC model. Apoptosis was detected with flow cytometry, TUNEL staining, and western blotting. Cardiac function was measured using echocardiography. Mitochondrial function was measured using ATP assays, JC-1, and MitoSOX. Mitochondrial morphology was observed using MitoTracker staining and transmission electron microscopy. Colocalization of dynamin-related protein 1 (Drp-1) in mitochondria was examined using immunofluorescence. Phosphorylation levels of Drp-1 at Ser637 site were determined using western blotting analysis. We found that CVB3 infection impaired mitochondrial function as evidenced by increased mitochondrial ROS production, decreased ATP production and mitochondrial membrane potential, induced myocardial apoptosis and damage, and decreased myocardial function. These effects of CVB3 infection were attenuated by inhibition of calpain both by PD150606 treatment and calpastatin overexpression. Furthermore, CVB3-induced mitochondrial dysfunction was associated with the accumulation of Drp-1 in the outer membrane of mitochondria and subsequent increase in mitochondrial fission. Mechanistically, calpain cleaved and activated calcineurin A, which dephosphorylated Drp-1 at Ser637 site and promoted its accumulation in the mitochondria, leading to mitochondrial fission and dysfunction. In summary, calpain inhibition attenuated CVB3-induced myocarditis by reducing mitochondrial fission, thereby inhibiting cardiomyocyte apoptosis.

AKAP150 mobilizes cPKC-dependent cardiac glucotoxicity

2014 ◽  
Vol 307 (4) ◽  
pp. E384-E397 ◽  
Author(s):  
Chao Zeng ◽  
Jinyi Wang ◽  
Na Li ◽  
Mingzhi Shen ◽  
Dongjuan Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
High Glucose ◽  
Myocardial Dysfunction ◽  
Left Ventricular ◽  
Cardiomyocyte Apoptosis ◽  
Neonatal Rat ◽  
Tunel Staining ◽  
Rat Cardiomyocytes ◽  
Intramyocardial Injection ◽  
And Oxidative Stress

Activation of conventional PKCs (cPKC) is a key signaling that directs the cardiac toxicity of hyperglycemia. AKAP150, a scaffold protein of the A-kinase anchoring proteins (AKAPs) family, is less defined regarding its capability to anchor and regulate cardiac cPKC signaling. This study was designed to investigate the role of AKAP150 in cPKC-mediated cardiac glucotoxicity. In cardiac tissues from streptozotocin-induced diabetic rats and high-glucose-treated neonatal rat cardiomyocytes, both mRNA and protein levels of AKAP150 increased significantly, and marked elevations were observed in cPKC activity and both expression and phosphorylation levels of p65 NF-κB and p47phox. AKAP150 knockdown was established via intramyocardial injection in vivo and transfection in vitro of adenovirus carrying AKAP150-targeted shRNA. Downregulation of AKAP150 reversed diabetes-induced diastolic dysfunction as manifested by decreased left ventricular end-diastolic diameter and early/late mitral diastolic wave ratio. AKAP150 inhibition also abrogated high-glucose-induced cardiomyocyte apoptosis (TUNEL staining and annexin V/propidium iodide flow cytometry) and oxidative stress (ROS production, NADPH oxidase activity, and lipid peroxidation). More importantly, reduced AKAP150 expression significantly inhibited high-glucose-induced membrane translocation and activation of cPKC and suppressed the increases in the phosphorylation of p65 NF-κB and p47phox. Immunofluorescent coexpression and immunoprecipitation indicated enhanced anchoring of AKAP150 with cPKC within the plasma membrane under hyperglycemia, and AKAP150 preferentially colocalized and functionally bound with PKCα and -β isoforms. These results suggest that cardiac AKAP150 positively responds to hyperglycemia and enhances the efficiency of glucotoxicity signaling through a cPKC/p47phox/ROS pathway that induces myocardial dysfunction, cardiomyocyte apoptosis, and oxidative stress.

Abstract 12526: AKAP150-Mobilized PKC Activation Mediates Myocardial Dysfunction in Diabetes

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Zeng Chao ◽  
Jinyi Wang ◽  
Na Li ◽  
Mingzhi Shen ◽  
Haichang Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
High Glucose ◽  
Myocardial Dysfunction ◽  
Left Ventricular ◽  
Cardiomyocyte Apoptosis ◽  
Neonatal Rat ◽  
Tunel Staining ◽  
Rat Cardiomyocytes ◽  
Intramyocardial Injection ◽  
And Oxidative Stress

Background: Chronic activation of conventional PKC (cPKC) is a key signaling that directs the cardiac toxicity of hyperglycemia. AKAP150, a scaffold protein of the A-kinase anchoring proteins (AKAPs) family, is less defined regarding its capability to anchor and regulate cPKC signaling in cardiomyocytes. This study was aimed to investigate the role of AKAP150 in cPKC-mediated cardiac injury in diabetes. Methods and Results: In cardiac tissues from streptozotocin-induced diabetic rats and high-glucose treated neonatal rat cardiomyocytes, expression of AKAP150 increased significantly at both mRNA and protein levels, with a marked elevation in expression and activity of cPKC and phosphorylation levels of p65NF-κB and p47phox. AKAP150 knockdown was established via intramyocardial injection in vivo and transfection in vitro of adenovirus carrying AKAP150 targeted shRNA. Downregulation of AKAP150 reversed diabetes-induced diastolic dysfunction, as evidenced by decreased left ventricular end-diastolic diameter and early/late mitral diastolic wave ratio. AKAP150 inhibition also abrogated high-glucose induced cardiomyocyte apoptosis (TUNEL staining and annexin V/PI flow cytometry) and oxidative stress (ROS production, NADPH oxidase activity and lipid peroxidation). More importantly, reduced AKAP150 expression significantly reversed high-glucose induced membrane translocation and activation of cPKC, and inhibited phosphorylation of p65NF-κB and p47phox. Immunofluorescent co-expression and immunoprecipitation analysis indicated enhanced anchoring of AKAP150 with cPKC within the plasma membrane in both diabetic myocardium and high-glucose treated cardiomyocytes. Further studies using antibodies and specific inhibitors against different cPKC isoforms revealed that AKAP150 preferentially co-localized and functionally bound with PKC α and β, which are the major isoforms responsible for cardiac glucotoxicity. Conclusions: Cardiac AKAP150 positively responds to hyperglycemic stimuli and functions to enhance the efficiency of glucotoxicity signaling through a cPKC/p47phox/ROS pathway that induces myocardial dysfunction, cardiomyocyte apoptosis and oxidative stress.

scholarly journals A20 (TNFAIP3) alleviates viral myocarditis through ADAR1/miR-1a-3p-dependent regulation

2022 ◽  
Vol 22 (1) ◽  
Author(s):  
Bin Li ◽  
Xing Xie
Keyword(s):  
Creatine Kinase ◽  
Rna Binding ◽  
Viral Myocarditis ◽  
Neonatal Rat ◽  
Coxsackie Virus ◽  
Luciferase Reporter ◽  
Cell Culture Supernatant ◽  
Tunel Staining ◽  
Rat Cardiomyocytes ◽  
Cellular Models

Abstract Objective To investigate the effect of A20 and how A20 is regulated in viral myocarditis (VMC). Methods BABL/C mice, primary neonatal rat cardiomyocytes and H9c2 cells were infected with Coxsackie virus B3 (CVB3) to establish animal and cellular models of VMC. H&E staining revealed the pathologic condition of myocardium. ELISA measured the serum levels of creatine kinase, creatine kinase isoenzyme and cardiac troponin I. The effects of A20, miR-1a-3p and ADAR1 were investigated using gain and loss of function approaches. ELISA measured the levels of IL-6, IL-18 and TNF-α in serum or cell culture supernatant. TUNEL staining and flow cytometry assessed the apoptosis of myocardium and cardiomyocytes, respectively. RNA-binding protein immunoprecipitation and dual-luciferase reporter assays verified the binding between A20 and miR-1a-3p. Co-immunoprecipitation assay verified the binding between ADAR1 and Dicer. Results A20 was underexpressed and miR-1a-3p was overexpressed in the myocardium of VMC mice as well as in CVB3-infected cardiomyocytes. Overexpression of A20 suppressed cardiomyocyte inflammation and apoptosis in vivo and in vitro. miR-1a-3p promoted CVB3-induced inflammation and apoptosis in cardiomyocytes by binding to A20. The expression of miR-1a-3p was regulated by ADAR1. ADAR1 promoted the slicing of miR-1a-3p precursor by binding to Dicer. Conclusion A20, regulated by ADAR1/miR-1a-3p, suppresses inflammation and cardiomyocyte apoptosis in VMC.

Percutaneous Intracoronary Delivery of Plasma Extracellular Vesicles Protects the Myocardium Against Ischemia-Reperfusion Injury in Canis

Hypertension ◽  
2021 ◽  
Vol 78 (5) ◽  
pp. 1541-1554
Author(s):  
Hongyun Wang ◽  
Rusitanmujiang Maimaitiaili ◽  
Jianhua Yao ◽  
Yuling Xie ◽  
Sujing Qiang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Embryonic Stem Cell ◽  
Human Embryonic Stem Cell ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Embryonic Stem ◽  
Cardiomyocyte Apoptosis ◽  
Neonatal Rat ◽  
Rat Cardiomyocytes ◽  
Neonatal Rat Cardiomyocytes

Plasma circulating extracellular vesicles (EVs) have been utilized as a potential therapeutic strategy to treat ischemic disease through intramyocardial injection (efficient but invasive) or tail vein injection (noninvasive but low cardiac retention). An effective and noninvasive delivery of EVs for future clinical use is necessary. The large animal (canine) model was complemented with a murine ischemia-reperfusion injury (IRI) model, as well as H9 human embryonic stem cell–induced cardiomyocytes or neonatal rat cardiomyocytes to investigate the effective delivery method and the role of plasma EVs in the IRI model. We further determine the crucial molecule within EVs that confers the cardioprotective role in vivo and in vitro and investigate the efficiency of CHP (cardiac homing peptide)-linked EVs in alleviating IRI. D-SPECT imaging showed that percutaneous intracoronary delivery of EVs reduced infarct extent in dogs. CHP-EVs further reduced IRI-induced cardiomyocyte apoptosis in mice and neonatal rat cardiomyocytes. Mechanistically, administration of EVs by percutaneous intracoronary delivery (in dog) and myocardial injection (in mice) just before reperfusion reduced infarct size of IRI by increasing miR-486 levels. miR-486–deleted EVs exacerbated oxygen-glucose deprivation/reoxygenation–induced human embryonic stem cell–induced cardiomyocytes and neonatal rat cardiomyocyte apoptosis. EV-miR-486 inhibited the PTEN (phosphatase and tensin homolog deleted on chromosome ten) expression and then promoted AKT (protein kinase B) activation in human embryonic stem cell–induced cardiomyocytes and neonatal rat cardiomyocytes. In conclusion, plasma-derived EVs convey miR-486 to the myocardium and attenuated IRI-induced infarction and cardiomyocyte apoptosis. CHP strategy was effective to improve cardiac retention of EVs in mice (in vivo) and dogs (ex vivo).

Role of myofibrillogenesis regulator-1 in myocardial hypertrophy

2006 ◽  
Vol 290 (1) ◽  
pp. H279-H285 ◽  
Author(s):  
Xiuhua Liu ◽  
Tianbo Li ◽  
Sheng Sun ◽  
Feifei Xu ◽  
Yiguang Wang
Keyword(s):  
Rna Interference ◽  
Cardiac Hypertrophy ◽  
Protein Expression ◽  
Western Blotting ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Heart Weight ◽  
Homologous Gene ◽  
Ang Ii ◽  
Rat Cardiomyocytes

Myofibrillogenesis regulator-1 (MR-1) is a novel homologous gene, identified from a human skeletal muscle cDNA library, that interacts with contractile proteins and exists in human myocardial myofibrils. The present study investigated MR-1 protein expression in hypertrophied myocardium and MR-1 involvement in cardiac hypertrophy. Cardiac hypertrophy was induced by abdominal aortic stenosis (AAS) in Sprague-Dawley rats. Left ventricular (LV) hypertrophy was assessed by the ratio of LV wet weight to whole heart weight (LV/HW) or LV weight to body weight (LV/BW). Rat MR-1 (rMR-1) expression in the myocardium was detected by immunohistochemical and Western blotting analysis. Hypertrophy was induced by ANG II incubation in cultured neonatal rat cardiomyocytes. The effect of rMR-1 RNA interference on ANG II-induced hypertrophy was studied by transfection of cardiomyocytes with an RNA interference plasmid, pSi-1, which targets rMR-1. Hypertrophy in cardiomyocytes was assessed by [3H]Leu incorporation and myocyte size. rMR-1 protein expression in cardiomyocytes was detected by Western blotting. We found that AAS resulted in a significant increase in LV/HW and LV/BW: 89% and 86%, respectively ( P < 0.01). Immunohistochemistry and Western blot analysis demonstrated upregulated rMR-1 protein expression in hypertrophic myocardium. ANG II induced a 24% increase in [3H]Leu incorporation and a 65.8% increase in cell size compared with control cardiomyocytes ( P < 0.01), which was prevented by treatment with losartan, an angiotensin (AT1) receptor inhibitor, or transfection with pSi-1. rMR-1 expression increased in ANG II-induced hypertrophied cardiomyocytes, and pSi-1 transfection abolished the upregulation. These findings suggest that MR-1 is associated with cardiac hypertrophy in rats in vivo and in vitro.

scholarly journals Overexpression of TIMP3 Protects Against Cardiac Ischemia/Reperfusion Injury by Inhibiting Myocardial Apoptosis Through ROS/Mapks Pathway

2017 ◽  
Vol 44 (3) ◽  
pp. 1011-1023 ◽  
Author(s):  
Hui Liu ◽  
Xibo Jing ◽  
Aiqiao Dong ◽  
Baobao Bai ◽  
Haiyan Wang
Keyword(s):  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Neonatal Rat ◽  
Tunel Staining ◽  
Ros Production ◽  
Rat Cardiomyocytes ◽  
Doxorubicin Treatment ◽  
Myocardial Apoptosis

Background/Aims: Myocardial ischemia/reperfusion (I/R) injury remains a great challenge in clinical therapy. Tissue inhibitor of metalloproteinases 3 (TIMP3) plays a crucial role in heart physiological and pathophysiological processes. However, the effects of TIMP3 on I/R injury remain unknown. Methods: C57BL/6 mice were infected with TIMP3 adenovirus by local delivery in myocardium followed by I/R operation or doxorubicin treatment. Neonatal rat cardiomyocytes were pretreated with TIMP3 adenovirus prior to anoxia/reoxygenation (A/R) treatment in vitro. Histology, echocardiography, in vivo phenotypical analysis, flow cytometry and western blotting were used to investigate the altered cardiac function and underlying mechanisms. Results: The results showed that upregulation of TIMP3 in myocardium markedly inhibited myocardial infarct areas and the cardiac dysfunction induced by I/R or by doxorubicin treatment. TUNEL staining revealed that TIMP3 overexpression attenuated I/R-induced myocardial apoptosis, accompanied by decreased Bax/Bcl-2 ratio, Cleaved Caspase-3 and Cleaved Caspase-9 expression. In vitro, A/R-induced cardiomyocyte apoptosis was abrogated by pharmacological inhibition of reactive oxygen species (ROS) production or MAPKs signaling. Attenuation of ROS production reversed A/R-induced MAPKs activation, whereas MAPKs inhibitors showed on effect on ROS production. Furthermore, in vivo or in vitro overexpression of TIMP3 significantly inhibited I/R- or A/R-induced ROS production and MAPKs activation. Conclusion: Our findings demonstrate that TIMP3 upregulation protects against cardiac I/R injury through inhibiting myocardial apoptosis. The mechanism may be related to inhibition of ROS-initiated MAPKs pathway. This study suggests that TIMP3 may be a potential therapeutic target for the treatment of I/R injury.

scholarly journals Repeated Aconitine Treatment Induced the Remodeling of Mitochondrial Function via AMPK–OPA1–ATP5A1 Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Li-Zhen Qiu ◽  
Wei Zhou ◽  
Lan-Xin Yue ◽  
Yi-Hao Wang ◽  
Fei-Ran Hao ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Mitochondrial Function ◽  
Positive Inotropic Effect ◽  
Neonatal Rat ◽  
Inotropic Effect ◽  
Mitochondrial Morphology ◽  
Repeated Treatment ◽  
Α Subunit ◽  
Compound C ◽  
Cardiotonic Effect

Aconitine is attracting increasing attention for its unique positive inotropic effect on the cardiovascular system, but underlying molecular mechanisms are still not fully understood. The cardiotonic effect always requires abundant energy supplement, which is mainly related to mitochondrial function. And OPA1 has been documented to play a critical role in mitochondrial morphology and energy metabolism in cardiomyocytes. Hence, this study was designed to investigate the potential role of OPA1-mediated regulation of energy metabolism in the positive inotropic effect caused by repeated aconitine treatment and the possible mechanism involved. Our results showed that repeated treatment with low-doses (0–10 μM) of aconitine for 7 days did not induce detectable cytotoxicity and enhanced myocardial contraction in Neonatal Rat Ventricular Myocytes (NRVMs). Also, we first identified that no more than 5 μM of aconitine triggered an obvious perturbation of mitochondrial homeostasis in cardiomyocytes by accelerating mitochondrial fusion, biogenesis, and Parkin-mediated mitophagy, followed by the increase in mitochondrial function and the cellular ATP content, both of which were identified to be related to the upregulation of ATP synthase α-subunit (ATP5A1). Besides, with compound C (CC), an inhibitor of AMPK, could reverse aconitine-increased the content of phosphor-AMPK, OPA1, and ATP5A1, and the following mitochondrial function. In conclusion, this study first demonstrated that repeated aconitine treatment could cause the remodeling of mitochondrial function via the AMPK–OPA1–ATP5A1 pathway and provide a possible explanation for the energy metabolism associated with cardiotonic effect induced by medicinal plants containing aconitine.

scholarly journals Activation of the M3AChR and Notch1/HSF1 Signaling Pathway by Choline Alleviates Angiotensin II-Induced Cardiomyocyte Apoptosis

2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Man Xu ◽  
Xue-Yuan Bi ◽  
Xiao-Rong Xue ◽  
Xing-Zhu Lu ◽  
Qiong-Ge Li ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Signaling Pathway ◽  
Nuclear Translocation ◽  
Cardiomyocyte Apoptosis ◽  
Neonatal Rat ◽  
In Vivo Studies ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Ang Ii ◽  
Rat Cardiomyocytes ◽  
Apoptosis Pathway

Angiotensin II- (Ang II-) induced cardiac hypertrophy and apoptosis are major characteristics of early-stage heart failure. Choline exerts cardioprotective effects; however, its effects on Ang II-induced cardiomyocyte apoptosis are unclear. In this study, the role and underlying mechanism of choline in regulating Ang II-induced cardiomyocyte apoptosis were investigated using a model of cardiomyocyte apoptosis, which was induced by exposing neonatal rat cardiomyocytes to Ang II (10−6 M, 48 h). Choline promoted heat shock transcription factor 1 (HSF1) nuclear translocation and the intracellular domain of Notch1 (NICD) expression. Consequently, choline attenuated Ang II-induced increases in mitochondrial reactive oxygen species (mtROS) and promotion of proapoptotic protein release from mitochondria, including cytochrome c, Omi/high-temperature requirement protein A2, and second mitochondrial activator of caspases/direct inhibitor of apoptosis-binding protein with low P. The reversion of these events attenuated Ang II-induced increases in cardiomyocyte size and numbers of terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling-positive cells, presumably via type 3 muscarinic acetylcholine receptor (M3AChR). Indeed, downregulation of M3AChR or Notch1 blocked choline-mediated upregulation of NICD and nuclear HSF1 expression, as well as inhibited mitochondrial apoptosis pathway and cardiomyocyte apoptosis, indicating that M3AChR and Notch1/HSF1 activation confer the protective effects of choline. In vivo studies were performed in parallel, in which rats were infused with Ang II for 4 weeks to induce cardiac apoptosis. The results showed that choline alleviated cardiac remodeling and apoptosis of Ang II-infused rats in a manner related to activation of the Notch1/HSF1 pathway, consistent with the in vitro findings. Taken together, our results reveal that choline impedes oxidative damage and cardiomyocyte apoptosis by activating M3AChR and Notch1/HSF1 antioxidant signaling, and suggest a novel role for the Notch1/HSF1 signaling pathway in the modulation of cardiomyocyte apoptosis.

Abstract 347: Targeted FAK Activation in Cardiomyocytes Protects the Heart from Doxorubicin-Induced Cardiomyopathy

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Zhaokang Cheng ◽  
Laura A DiMichele ◽  
Zeenat S Hakim ◽  
Mauricio Rojas ◽  
Christopher P Mack ◽  
...  
Keyword(s):  
Ischemia Reperfusion ◽  
Posterior Wall ◽  
Neonatal Rat ◽  
Tunel Staining ◽  
Littermate Control ◽  
Rat Cardiomyocytes ◽  
Enhanced Expression ◽  
Myocyte Apoptosis ◽  
Novel Strategy ◽  
Induced Apoptosis

OBJECTIVE: We recently reported that cardiac-restricted activation of focal adhesion kinase (FAK) attenuated myocardial injury following ischemia/reperfusion using transgenic mice that express a FAK variant (termed SuperFAK) in cardiomyocytes. Here we interrogated whether targeted elevation of myocardial FAK activity could protect against cardiomyopathy induced by the highly effective chemotherapy drug Doxorubicin (DOX). METHODS AND RESULTS: Eight- to twelve-week-old male mice were given a single injection of DOX (20mg/kg, i.p.). At day 14, SuperFAK mice exhibited better survival (62.5%, n=8) than littermate control mice (37.5%, n=8). Serial echocardiography revealed that DOX administration markedly decreased cardiac function and ventricular wall thickness in control mice, whereas both parameters were better preserved in SuperFAK mice at day 5 (fractional shortening: 52.7±1.5% in SuperFAK vs . 38.9±3.7% in control, p <0.01; posterior wall end-systolic thickness: 1.83±0.12mm in SuperFAK vs . 1.43±0.12mm in control, p <0.05). Importantly, SuperFAK hearts exhibited a dramatic increase in FAK activity (as assessed by phospho-FAK Y397 immunoblotting) and a reduction in myocyte apoptosis (as assessed by TUNEL staining) in comparison with control hearts. DOX also induced apoptosis in cultured neonatal rat cardiomyocytes and adenoviral-mediated expression of SuperFAK ameliorated DOX-induced toxicity as assessed by MTT and TUNEL assays. Over-expression of SuperFAK also enhanced expression of the pro-survival NF-κB transcriptional targets Bcl-2, Bcl-xl, and X-linked inhibitor of apoptosis, whereas pharmacologically blockade of the NF-κB pathway completely abolished the up-regulation of these anti-apoptotic molecules by SuperFAK. CONCLUSIONS: Ventricular dysfunction and myocyte apoptosis induced by DOX was attenuated by enhancing cardiac FAK activity, which may represent a novel strategy to reduce anthracycline mediated cardiotoxicity in cancer patients undergoing chemotherapy.

scholarly journals ZP2495 Protects against Myocardial Ischemia/Reperfusion Injury in Diabetic Mice through Improvement of Cardiac Metabolism and Mitochondrial Function: The Possible Involvement of AMPK-FoxO3a Signal Pathway

2018 ◽  
Vol 2018 ◽  
pp. 1-15 ◽  
Author(s):  
Shuang Li ◽  
Hao Wu ◽  
Dong Han ◽  
Mingming Zhang ◽  
Na Li ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Cardiac Function ◽  
Mitochondrial Function ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Neonatal Rat ◽  
Ros Generation ◽  
Mitochondrial Morphology ◽  
Signal Pathways ◽  
The Impact

Coronary heart disease patients with type 2 diabetes were subject to higher vulnerability for cardiac ischemia-reperfusion (I/R) injury. This study was designed to evaluate the impact of ZP2495 (a glucagon-GLP-1 dual-agonist) on cardiac function and energy metabolism after myocardial I/R injury in db/db mice with a focus on mitochondrial function. C57BLKS/J-lepr+/lepr+ (BKS) and db/db mice received 4-week treatment of glucagon, ZP131 (GLP-1 receptor agonist), or ZP2495, followed by cardiac I/R injury. The results showed that cardiac function, cardiac glucose metabolism, cardiomyocyte apoptosis, cardiac mitochondrial morphology, and energetic transition were improved or ameliorated by ZP2495 to a greater extent than that of glucagon and ZP131. In vitro study showed that ZP2495, rather than glucagon, alleviated mitochondrial depolarization, cytochrome C release, and mitochondria ROS generation in neonatal rat ventricular myocytes subjected to high-glucose and simulated I/R injury conditions, the effects of which were weaker in the ZP131 group. Furthermore, the expressions of Akt, FoxO3a, and AMPK phosphorylation were elevated by ZP2495 to a greater extent than that of ZP131. In conclusion, ZP2495 may contribute to the improvement of cardiac function and energy metabolism in db/db mice after myocardial I/R injury by improving mitochondrial function possibly through Akt/FoxO3a and AMPK/FoxO3a signal pathways.

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