scholarly journals Thymoquinone Attenuates Myocardial Ischemia/Reperfusion Injury Through Activation of SIRT1 Signaling

2018 ◽  
Vol 47 (3) ◽  
pp. 1193-1206 ◽  
Author(s):  
Yunyang Lu ◽  
Yingda Feng ◽  
Dan Liu ◽  
Zhiran Zhang ◽  
Kai Gao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Ischemia ◽  
Signaling Pathway ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Cardioprotective Effect ◽  
Neonatal Rat ◽  
Rat Cardiomyocytes ◽  
Production Of Hydrogen ◽  
Myocardial Ischemia Reperfusion

Background/Aims: Myocardial ischemia/reperfusion (MI/R) injury is a leading factor responsible for damage in myocardial infarction, resulting in additional injury to cardiac tissues involved in oxidative stress, inflammation, and apoptosis. Thymoquinone (TQ), the main constituent of Nigella sativa L. seeds, has been reported to possess various biological activities. However, few reports regarding myocardial protection are available at present. Therefore, this study was conducted aiming to investigate the protective effect of TQ against MI/R injury and to clarify its potential mechanism. Methods: MI/R injury models of isolated rat hearts and neonatal rat cardiomyocytes were established. The Langendorff isolated perfused heart system, triphenyltetrazolium chloride staining, gene transfection, TransLaser scanning confocal microscopy, and western blotting were employed to evaluate the cardioprotection effect of TQ against MI/R injury. Results: Compared with the MI/R group, TQ treatment could remarkably improve left ventricular function, decrease myocardial infarct size and production of lactate dehydrogenase (LDH), and attenuate mitochondrial oxidative damage by elevating superoxide dismutase (SOD) activity and reducing production of hydrogen peroxide (H2O2) and malonaldehyde (MDA). Moreover, the cardioprotective effect of TQ was accompanied by up-regulated expression of SIRT1 and inhibition of p53 acetylation. Additionally, TQ treatment could also enhance mitochondrial function and reduce the number of apoptotic cardiomyocytes. Nonetheless, the cardioprotective effect of TQ could be mitigated by SIRT1 inhibitor sirtinol and SIRT1 siRNA, respectively, which was achieved through inhibition of the SIRT1 signaling pathway. Conclusions: The findings in this study demonstrate that TQ is efficient in attenuating MI/R injury through activation of the SIRT1 signaling pathway, which can thus reduce mitochondrial oxidative stress damage and cardiomyocyte apoptosis.

scholarly journals Honokiol Ameliorates Myocardial Ischemia/Reperfusion Injury in Type 1 Diabetic Rats by Reducing Oxidative Stress and Apoptosis through Activating the SIRT1-Nrf2 Signaling Pathway

2018 ◽  
Vol 2018 ◽  
pp. 1-16 ◽  
Author(s):  
Bin Zhang ◽  
Mengen Zhai ◽  
Buying Li ◽  
Zhenhua Liu ◽  
Kaifeng Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Ischemia ◽  
Signaling Pathway ◽  
Nuclear Translocation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Reactive Oxygen Species Generation ◽  
Nrf2 Signaling Pathway ◽  
Myocardial Ischemia Reperfusion

Reducing oxidative stress is a crucial therapeutic strategy for ameliorating diabetic myocardial ischemia/reperfusion (MI/R) injury. Honokiol (HKL) acts as an effective cardioprotective agent for its strong antioxidative activity. However, its roles and underlying mechanisms against MI/R injury in type 1 diabetes (T1D) remain unknown. Since SIRT1 and Nrf2 are pivotal regulators in diabetes mellitus patients suffering from MI/R injury, we hypothesized that HKL ameliorates diabetic MI/R injury via the SIRT1-Nrf2 signaling pathway. Streptozotocin-induced T1D rats and high-glucose-treated H9c2 cells were exposed to HKL, with or without administration of the SIRT1 inhibitor EX527, SIRT1 siRNA, or Nrf2 siRNA, and then subjected to I/R operation. We found that HKL markedly improved the postischemic cardiac function, decreased the infarct size, reduced the myocardial apoptosis, and diminished the reactive oxygen species generation. Intriguingly, HKL remarkably activated SIRT1 signaling, enhanced Nrf2 nuclear translocation, increased antioxidative signaling, and decreased apoptotic signaling. However, these effects were largely abolished by EX527 or SIRT1 siRNA. Additionally, our cellular experiments showed that Nrf2 siRNA blunted the cytoprotective effects of HKL, without affecting SIRT1 expression and activity. Collectively, these novel findings indicate that HKL abates MI/R injury in T1D by ameliorating myocardial oxidative damage and apoptosis via the SIRT1-Nrf2 signaling pathway.

scholarly journals Cardioprotective Effect of the Aqueous Extract of Lavender Flower against Myocardial Ischemia/Reperfusion Injury

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Dong Wang ◽  
Xin Guo ◽  
Mingjie Zhou ◽  
Jichun Han ◽  
Bo Han ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Ischemia ◽  
Infarct Size ◽  
Aqueous Extract ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Myocardial Infarct Size ◽  
Myocardial Oxidative Stress ◽  
Myocardial Ischemia Reperfusion

This study was conducted to evaluate the cardioprotective property of the aqueous extract of lavender flower (LFAE). The myocardial ischemia/reperfusion (I/R) injury of rat was prepared by Langendorff retrograde perfusion technology. The heart was preperfused with K-H solution containing LFAE for 10 min before 20 minutes global ischemia, and then the reperfusion with K-H solution was conducted for 45 min. The left ventricular developed pressure (LVDP) and the maximum up/downrate of left ventricular pressure (±dp/dtmax) were recorded by physiological recorder as the myocardial function and the myocardial infarct size was detected by TTC staining. Lactate dehydrogenase (LDH) and creatine kinase (CK) activities in the effluent were measured to determine the myocardial injury degree. The superoxide anion dismutase (SOD) and malondialdehyde (MDA) in myocardial tissue were detected to determine the oxidative stress degree. The results showed that the pretreatment with LFAE significantly decreased the myocardial infarct size and also decreased the LDH, CK activities, and MDA level, while it increased the LVDP, ±dp/dtmax, SOD activities, and the coronary artery flow. Our findings indicated that LFAE could provide protection for heart against the I/R injury which may be related to the improvement of myocardial oxidative stress states.

scholarly journals Dexmedetomidine Protects against Myocardial Ischemia/Reperfusion Injury by Ameliorating Oxidative Stress and Cell Apoptosis through the Trx1-Dependent Akt Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Zhi-lin Wu ◽  
Jacques Robert Jeppe Davis ◽  
Yi Zhu
Keyword(s):  
Oxidative Stress ◽  
Myocardial Ischemia ◽  
Cardiac Function ◽  
Cell Apoptosis ◽  
Ischemia Reperfusion ◽  
Cardioprotective Effect ◽  
Akt Pathway ◽  
Rat Hearts ◽  
Myocardial Ischemia Reperfusion ◽  
Isolated Rat

Dexmedetomidine (Dex) was reported to reduce oxidative stress and protect against myocardial Ischemia/Reperfusion (I/R) injury. However, the molecular mechanism involved in its antioxidant property is not fully elucidated. The present study was aimed at investigating whether the Trx1/Akt pathway participated in the cardioprotective effect of Dex. In the present study, I/R-induced myocardial injury in isolated rat hearts and OGD/R-induced injury in H9c2 cardiomyocytes were established. Our findings suggested that Dex ameliorated myocardial I/R injury by improving cardiac function, reducing myocardial apoptosis and oxidative stress, which was manifested by increased GSH and SOD contents, decreased ROS level, and MDA generation in both the isolated rat hearts and OGD/R-treated H9C2 cells. More importantly, it was found that the level of Trx1 was preserved, and Akt phosphorylation was significantly upregulated by Dex treatment. However, these effects of Dex were abolished by PX-12 (a specific Trx1 inhibitor) administration. Taken together, this study suggests that Dex plays a protective role in myocardial I/R injury, improves cardiac function, and relieves oxidative stress and cell apoptosis. Furthermore, our results present a novel signaling mechanism that the cardioprotective effect of Dex is at least partly achieved through the Trx1-dependent Akt pathway.

scholarly journals Diabetes Upregulates Oxidative Stress and Downregulates Cardiac Protection to Exacerbate Myocardial Ischemia/Reperfusion Injury in Rats

Antioxidants ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 679
Author(s):  
Chen-Yen Chien ◽  
Ting-Jui Wen ◽  
Yu-Hsiuan Cheng ◽  
Yi-Ting Tsai ◽  
Chih-Yao Chiang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Ischemia ◽  
Caspase 3 ◽  
Diastolic Pressure ◽  
Myocardial Dysfunction ◽  
Ischemia Reperfusion ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Microvascular Reactivity ◽  
Myocardial Ischemia Reperfusion

Diabetes exacerbates myocardial ischemia/reperfusion (IR) injury by incompletely understood mechanisms. We explored whether diabetes diminished BAG3/Bcl-2/Nrf-2/HO-1-mediated cardioprotection and overproduced oxidative stress contributing to exaggerated IR injury. Streptozotocin-induced diabetes enhanced hyperglycemia, cardiac NADPH oxidase p22/p67 expression, malondialdehyde amount and leukocyte infiltration, altered the mesenteric expression of 4-HNE, CaSR, p-eNOS and BAG3 and impaired microvascular reactivity to the vasoconstrictor/vasodilator by a wire myography. In response to myocardial IR, diabetes further depressed BAG3/Bcl-2/Nrf-2/HO-1 expression, increased cleaved-caspase 3/poly(ADP-ribose) polymerase (PARP)/TUNEL-mediated apoptosis and exacerbated IR-induced left ventricular dysfunction characterized by further depressed microcirculation, heart rate, left ventricular systolic pressure and peak rate of pressure increase/decrease (±dp/dt) and elevated left ventricular end-diastolic pressure (LVEDP) and Evans blue-2,3,5-triphenyltetrazolium chloride-stained infarct size in diabetic hearts. Our results implicated diabetes exacerbated IR-induced myocardial dysfunction through downregulated BAG3/Bcl-2/Nrf-2/HO-1 expression, increased p22/p67/caspase 3/PARP/apoptosis-mediated oxidative injury and impaired microvascular reactivity.

Insulin attenuates myocardial ischemia/reperfusion injury via reducing oxidative/nitrative stress

2010 ◽  
Vol 298 (4) ◽  
pp. E871-E880 ◽  
Author(s):  
Lele Ji ◽  
Feng Fu ◽  
Lihua Zhang ◽  
Wenchong Liu ◽  
Xiaoqing Cai ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Cardioprotective Effect ◽  
Male Rats ◽  
No Production ◽  
Arterial Blood ◽  
Nitrative Stress ◽  
Enos Phosphorylation ◽  
Myocardial Ischemia Reperfusion

It is well known that insulin possesses a cardioprotective effect and that insulin resistance is closely related to cardiovascular diseases. Peroxynitrite (ONOO−) formation may trigger oxidative/nitrative stress and represent a major cytotoxic effect in heart diseases. This study was designed to investigate whether insulin attenuates ONOO− generation and oxidative/nitrative stress in acute myocardial ischemia/reperfusion (MI/R). Adult male rats were subjected to 30 min of myocardial ischemia and 3 h of reperfusion. Rats randomly received vehicle, insulin, or insulin plus wortmannin. Arterial blood pressure and left ventricular pressure were monitored throughout the experiment. Insulin significantly improved cardiac functions and reduced myocardial infarction, apoptotic cell death, and blood creatine kinase/lactate dehydrogenase levels following MI/R. Myocardial ONOO− formation was significantly attenuated after insulin treatment. Moreover, insulin resulted in a significant increase in Akt and endothelial nitric oxide (NO) synthase (eNOS) phosphorylation, NO production, and antioxidant capacity in ischemic/reperfused myocardial tissue. On the other hand, insulin markedly reduced MI/R-induced inducible NOS (iNOS) and gp91phox expression in cardiac tissue. Inhibition of insulin signaling with wortmannin not only blocked the cardioprotection of insulin but also markedly attenuated insulin-induced antioxidative/antinitrative effect. Furthermore, the suppression on ONOO− formation by either insulin or an ONOO− scavenger uric acid reduced myocardial infarct size in rats subjected to MI/R. We concluded that insulin exerts a cardioprotective effect against MI/R injury by blocking ONOO− formation. Increased physiological NO production (via eNOS phosphorylation) and superoxide anion reduction contribute to the antioxidative/antinitrative effect of insulin, which can be reversed by inhibiting phosphatidylinositol 3′-kinase. These results provide important novel information on the mechanisms of cardiovascular actions of insulin.

Abstract 1490: The Targeting Of Cyclophilin D By RNA Interference As A Novel Therapeutic Strategy Against Myocardial Ischemia/Reperfusion Injury

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Masashi Kato ◽  
Masaharu Akao ◽  
Takeru Makiyama ◽  
Madoka Matsumoto-Ida ◽  
Moritake Iguchi ◽  
...  
Keyword(s):  
Rna Interference ◽  
Myocardial Ischemia ◽  
Ischemia Reperfusion ◽  
Neonatal Rat ◽  
Cyclophilin D ◽  
Rat Cardiomyocytes ◽  
Two Photon ◽  
Rat Hearts ◽  
Myocardial Ischemia Reperfusion

Background- An opening of the mitochondrial permeability transition pore (MPTP), which leads to loss of mitochondrial membrane potential (ΔΨ m ) and mitochondrial dysfunction, is the earliest event that commits cells to death, and this process is potentially a prime target for therapeutic intervention against myocardial ischemia/reperfusion. We examined the effects of genetic knock-down of cyclophilin D (CypD), one of the putative components of MPTP, using RNA interference. Methods and Results- We created an adenovirus carrying short interfering RNA (siRNA) which inactivates CypD. Transduction of siRNA-CypD in cultured neonatal rat cardiomyocytes achieved 68% reduction in mRNA and 61% reduction in protein levels, and suppressed cell death induced by H 2 O 2 (100μM) as assessed by cell viability assay. It also protected against ΔΨ m loss, as assessed by both time-lapse confocal microscopy and fluorescence-activated cell sorter analysis of cardiomyocytes loaded with an indicator of ΔΨ m, tetramethylrhodamine ethylester (TMRE). To further investigate the effects in vivo, we monitored the spatio-temporal changes of ΔΨ m in perfused rat hearts subjected to ischemia/reperfusion, using the real-time two-photon confocal imaging system which we recently developed. Briefly, adult rats received direct intramyocardial injections of the siRNA-CypD adenovirus. 3–5 days after injection, the rat hearts were removed and perfused in Langendorff mode. After loading TMRE, the hearts underwent two-photon imaging under excitation with 810 nm line of a Ti:Sapphire laser. Ischemia was achieved by clamping the perfusion line, and reperfusion was achieved by releasing the clamp. The virus contained an expression cassette of green fluorescent protein, allowing us to distinguish transduced cells and non-transduced cells. The progressive loss of ΔΨ m induced by myocardial ischemia/ reperfusion was significantly suppressed in siRNA-CypD-transduced cells, compared with non-transduced cells. Conclusions- Targeting CypD by RNA interference protects against oxidant-induced cardiomyocyte injury in vitro, and myocardial ischemia/reperfusion in vivo, implicating CypD as a promising molecular target for anti-ischemia/reperfusion therapy.

scholarly journals Dexmedetomidine postconditioning suppresses myocardial ischemia/reperfusion injury by activating the SIRT1/mTOR axis

2020 ◽  
Vol 40 (5) ◽  
Author(s):  
Xiong Zhang ◽  
Yongxing Li ◽  
Yong Wang ◽  
Yuerong Zhuang ◽  
Xiaojie Ren ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Ischemia ◽  
Signaling Pathway ◽  
Ischemia Reperfusion ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Tetrazolium Chloride ◽  
Inflammatory Reactions ◽  
Sirt1 Inhibitor ◽  
Myocardial Ischemia Reperfusion

Abstract Myocardial ischemia/reperfusion (MI/R) triggers a complicated chain of inflammatory reactions. Dexmedetomidine (Dex) has been reported to be important in myocardial disorders. We evaluated the role of Dex in MI/R injury via the silent information regulator factor 2-related enzyme 1 (SIRT1)/mammalian target of rapamycin (mTOR) signaling pathway. First, Dex was immediately injected into rat models of MI/R injury during reperfusion. After Evans Blue-triphenyl tetrazolium chloride (TTC) and Hematoxylin–Eosin (H-E) staining, MI/R injury was observed. The extracted serum and myocardial tissues were used to detect oxidative stress and the inflammatory response. Western blot analysis was performed to evaluate MI/R autophagy and the levels of proteins associated with the SIRT1/mTOR axis. The effects of the combination of Dex and SIRT1 inhibitor EX527 on MI/R injury and autophagy were evaluated. Finally, the mechanism of Dex was tested, and autophagy levels and the levels of proteins associated with the SIRT1/mTOR signaling pathway were assessed in MI/R rats. The results of the present study suggested that Dex relieved MI/R injury, reduced cardiomyocyte apoptosis, oxidative stress and inflammatory reactions, up-regulated the SIRT1/mTOR axis and decreased overautophagy in MI/R rats. SIRT1 inhibitor EX527 attenuated the protective effects of Dex. Our study demonstrated that Dex alleviated MI/R injury by activating the SIRT1/mTOR axis. This investigation may offer new insight into the treatment of MI/R injury.

scholarly journals Fisetin Attenuates Myocardial Ischemia-Reperfusion Injury by Activating the Reperfusion Injury Salvage Kinase (RISK) Signaling Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Karthi Shanmugam ◽  
Sri Rahavi Boovarahan ◽  
Priyanka Prem ◽  
Bhavana Sivakumar ◽  
Gino A Kurian
Keyword(s):  
Oxidative Stress ◽  
Myocardial Ischemia ◽  
Reperfusion Injury ◽  
Signaling Pathway ◽  
Isolated Heart ◽  
Ischemia Reperfusion ◽  
Cardioprotective Effect ◽  
Myocardial Infarct Size ◽  
Myocardial Oxidative Stress ◽  
Rat Hearts

Ischemia-reperfusion (I/R) injury is an unavoidable injury that occurs during revascularization procedures. In the previous study, we reported that fisetin is a natural flavonoid that attenuates I/R injury by suppressing mitochondrial oxidative stress and mitochondrial dysfunction. Though fisetin is reported as a GSK3β inhibitor, it remains unclear whether it attenuates myocardial ischemia by activating the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway, thereby inhibiting the downstream GSK3β, or by directly interacting with GSK3β while rendering its cardioprotection. In this study, the research team investigates the possible mechanism of action of fisetin while rendering its cardioprotective effect against myocardial I/R injury in rats. For this investigation, the team utilized two myocardial I/R models: Ligation of the left anterior descending artery and Langendorff isolated heart perfusion system. The latter has no neurohormonal influences. The PI3K inhibitor (Wortmannin, 0.015 mg/kg), GSK3β inhibitor (SB216763, 0.7 mg/kg), and fisetin (20 mg/kg) were administered intraperitoneally before inducing myocardial I/R. The result of this study reveals that the administration of fisetin decreases the myocardial infarct size, apoptosis, lactate dehydrogenase, and creatine kinase in serum\perfusate of the rat hearts subjected to I/R. However, the inhibition of PI3K with Wortmannin significantly reduced the cardioprotective effect of fisetin both in the ex vivo and vivo models. The administration of GSK3β inhibitor after the administration of fisetin and Wortmannin, re-establishing the cardioprotection, indicates the major role of PI3K in fisetin action. Changes in myocardial oxidative stress (level) and mitochondrial functional preservation of interfibrillar and subsarcolemmal mitochondria support the above findings. Hence, the team here reports that fisetin conferred its cardioprotection against I/R injury by activating the PI3K/Akt/GSK3β signaling pathway in rat hearts.

Abstract 338: Thioredoxin-Interacting Protein Contributes to Aggravated Myocardial Ischemia/Reperfusion Injury by Hyperglycemia

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Haifeng Zhang ◽  
Wenjuan Xing ◽  
Lele Ji ◽  
Hui Su ◽  
Xin Sun ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
P38 Mapk ◽  
Cell Apoptosis ◽  
Ischemia Reperfusion ◽  
Neonatal Rat ◽  
Interacting Protein ◽  
Rat Cardiomyocytes ◽  
Intramyocardial Injection ◽  
Thioredoxin Interacting Protein ◽  
Myocardial Ischemia Reperfusion

Hyperglycemia during acute myocardial infarction is common and associated with increased mortality. Thioredoxin-interacting protein (Txnip) is a modulator of cellular redox state and contributes to cell apoptosis. This study aimed to investigate whether hyperglycemia enhances Txnip expression and consequently exacerbates myocardial ischemia/reperfusion (MI/R) injury. Adult male SD rats were subjected to MI/R (30 min/4 h) and treated with saline or high glucose (HG, 500 g/L, 4 ml/kg/h, intravenously throughout the whole MI/R). In vitro study was performed on cultured neonatal rat cardiomyocytes subjected to simulated ischemia/reperfusion (SI/R) and incubated with HG (25 mM) or normal glucose (5.6 mM) medium. In vivo HG infusion significantly reduced the ± LV d P /dt max by 13.2 and 14.1% respectively (n=8, P <0.05), increased infarct size and myocardial apoptosis ( P <0.05) and increased superoxide accumulation ( P <0.01) compared with those in the saline group. Meanwhile, Txnip expression was enhanced (Ratio of Txnip/β-actin: 1.22 ± 0.16 vs. 0.92 ± 0.05 of MI/R+saline, n=6-8, P <0.05) whereas thioredoxin activity was inhibited (0.50 ± 0.05 vs. 1.41 ± 0.06 μmol/min/mg protein, P <0.01) following HG treatment in MI/R hearts. Additionally, HG significantly activated p38 MAPK and inhibited Akt in I/R hearts ( P <0.05). In cultured cardiomyocytes subjected to SI/R, HG incubation stimulated Txnip expression and reduced thioredoxin activity (n=6, P <0.05). Overexpression of Txnip enhanced HG-induced superoxide generation and aggravated cell apoptosis (n=6, P <0.05), while Txnip RNAi significantly blunted the deleterious effects of HG ( P <0.05). Moreover, inhibition of p38 MAPK or activation of Akt markedly blocked HG-induced Txnip expression in I/R cardiomyocytes. Most importantly, intramyocardial injection of Txnip siRNA markedly decreased Txnip expression and alleviated MI/R injury as evidenced by reduced infarction size (23.7 ± 1.6% vs. 43.1 ± 4.8%, n=6, P <0.05) and caspase 3 activity ( P <0.05) in HG-treated rats. Hyperglycemia enhances myocardial Txnip expression, possibly through reciprocally modulating p38 MAPK and Akt activation, leading to aggravated oxidative stress and subsequent amplification of cardiac injury following MI/R.

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