Systems pharmacology dissection of the anti-myocardial ischemia-reperfusion injury mechanism for Ganjiang Fuzi decoction

2022 ◽  
Author(s):  
Feng Xie ◽  
Nan Gou ◽  
Yue Ma ◽  
Ji Peng ◽  
Tiantian Zhang ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Oxidative Damage ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Vascular Endothelial ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Abstract Background: As the commonest form of ischemic heart diseases, the Myocardial Ischemia-Reperfusion injury (MI/RI) accounts for almost 50 percent of all deaths. The prevention and treatment of MI/RI while reducing the mortality of myocardial infarction has become a raging topic of research in the cardiovascular field. At present, there are no effective drugs for the treatment of MI/RI. Hence, it becomes imperative to identify or develop efficient lead compounds for treating MI/RI. It has been reported that the Ganjiang Fuzi Decoction (GFD) could be used for the effective treatment of MI/RI due to its promotion of vasodilation and vascular endothelial cell proliferation besides reducing the oxidative damage. Methods: The network pharmacological methods were used in this study, for analyzing the biological processes and the molecular mechanisms of the GFD for MI/RI treatment. In vitro and in vivo experiments were performed for verification of the results of the network pharmacological predictions. Results: Around 16 active components of GFD were discovered against MI/RI, where aconitine, 6-ginger, mesaconitine, and hypaconitine were the leading ones with regard to the degree value. Moreover, it was found that 88 MI/RI-related targets mainly involved six aspects, apoptosis, oxidative stress, inflammation, mitochondrial energy metabolism, and vasodilation. In vitro studies indicated the ability of the GFD to increase the survival rate, decrease the apoptosis rate, reduce oxidative damage, and increase the expression of HIF-1α, VEGF, and eNOS in hypoxia/reoxygenation(H/R) injured Rat Vascular Endothelial Cells (RVEC). The in vivo studies illustrated the capacity of the GFD to reduce the myocardial tissue damage and the infarction area, while increasing the expression of HIF-1α, VEGF, and eNOS in the MI/RI rats. Conclusions: The results of this study confirmed the anti-MI/RI role of the GFD through the activation of the HIF-1α signaling pathway, promotion of vascular proliferation and dilation, and the reduction in oxidative damage. The findings of this study would further provide experimental evidence for the application of the GFD in the treatment of MI/RI.

The cardioprotection of dihydrotanshinone I against myocardial ischemia–reperfusion injury via inhibition of arachidonic acid ω-hydroxylase

2016 ◽  
Vol 94 (12) ◽  
pp. 1267-1275 ◽  
Author(s):  
Yidan Wei ◽  
Meijuan Xu ◽  
Yi Ren ◽  
Guo Lu ◽  
Yangmei Xu ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Myocardial Ischemia ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Protective Effects ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Arachidonic acid (AA) is a precursor that is metabolized by several enzymes to many biological eicosanoids. Accumulating data indicate that the ω-hydroxylation metabolite of AA, 20-hydroxyeicosatetraenoic acid (20-HETE), is considered to be involved in the myocardial ischemia–reperfusion injury (MIRI). The inhibitors of AA ω-hydroxylase, however, are demonstrated to exhibit protective effects on MIRI. Dihydrotanshinone I (DI), a bioactive constituent of danshen, is proven to be a potent inhibitor of AA ω-hydroxylase by our preliminary study in vitro. The purpose of the present study was to investigate the cardioprotection of DI against MIRI and its effects on the concentrations of 20-HETE in vivo. Rats subjected to 30 min of ischemia followed by 24 h of reperfusion were assigned to intravenously receive vehicle (sham and ischemia–reperfusion), low (1 mg/kg), middle (2 mg/kg), or high (4 mg/kg) doses of DI before reperfusion. The results demonstrated that DI treatment could improve cardiac function, reduce infarct size, ameliorate the variations in myocardial zymogram and histopathological disorders, decrease 20-HETE generation, and regulate apoptosis-related protein in myocardial ischemia–reperfusion rats. These findings suggested DI could exert considerable cardioprotective action on MIRI by the attenuation of 20-HETE generation, subsequent myocardial injury, and apoptosis through inhibition on AA ω-hydroxylase.

scholarly journals Calenduloside E Ameliorates Myocardial Ischemia-Reperfusion Injury through Regulation of AMPK and Mitochondrial OPA1

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Min Wang ◽  
Rui-ying Wang ◽  
Jia-hui Zhou ◽  
Xue-heng Xie ◽  
Gui-bo Sun ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Mitochondrial Dynamics ◽  
Ischemia Reperfusion ◽  
Protective Effects ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Calenduloside E (CE) is a natural triterpenoid saponin isolated from Aralia elata (Miq.) Seem., a well-known traditional Chinese medicine. Our previous studies have shown that CE exerts cardiovascular protective effects both in vivo and in vitro. However, its role in myocardial ischemia/reperfusion injury (MIRI) and the mechanism involved are currently unknown. Mitochondrial dynamics play a key role in MIRI. This study investigated the effects of CE on mitochondrial dynamics and the signaling pathways involved in myocardial ischemia/reperfusion (MI/R). The MI/R rat model and the hypoxia/reoxygenation (H/R) cardiomyocyte model were established in this study. CE exerted significant cardioprotective effects in vivo and in vitro by improving cardiac function, decreasing myocardial infarct size, increasing cardiomyocyte viability, and inhibiting cardiomyocyte apoptosis associated with MI/R. Mechanistically, CE restored mitochondrial homeostasis against MI/R injury through improved mitochondrial ultrastructure, enhanced ATP content and mitochondrial membrane potential, and reduced mitochondrial permeability transition pore (MPTP) opening, while promoting mitochondrial fusion and preventing mitochondrial fission. However, genetic silencing of OPA1 by siRNA abolished the beneficial effects of CE on cardiomyocyte survival and mitochondrial dynamics. Moreover, we demonstrated that CE activated AMP-activated protein kinase (AMPK) and treatment with the AMPK inhibitor, compound C, abolished the protective effects of CE on OPA1 expression and mitochondrial function. Overall, this study demonstrates that CE is effective in mitigating MIRI by modulating AMPK activation-mediated OPA1-related mitochondrial fusion.

scholarly journals Platelet Membrane-Camouflaged Nanoparticles Carry microRNA inhibitor Against Myocardial Ischemia-Reperfusion Injury

2021 ◽  
Author(s):  
Tianyi Wang ◽  
Tingting Zhou ◽  
Mingming Xu ◽  
Xuechao Yang ◽  
Shuai He ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Plga Nanoparticles ◽  
Platelet Membrane ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Abstract Background The incidence of myocardial ischemia reperfusion injury (MIRI) is increasing year by year, and there is an urgent need to develop new treatment methods. Nrf2 is believed to play a protective role during MIRI and is regulated by microRNAs (miRNAs). Platelets are physiologically targeted to MIRI injury sites. The focus of this study is on platelet membranes, also called platelet membrane vesicles (PMVs), camouflaged PLGA nanoparticles, carrying microRNA inhibitors to regulate Nrf2, and play a therapeutic role during MIRI. Results First, we characterized the high transfection efficiency and low toxicity of PLGA in vitro, as well as the good targeting of PMVs in vivo; then, we found a microRNA (microRNA-155-5p) that effectively regulates Nrf2 in vitro, and confirmed its effect on cardiomyocyte apoptosis during MIRI; finally, PMVs camouflaged PLGA-miRNA complexes (PMVs@PLGA-miRNA complexes) were prepared and applied to MIRI treatment, and it was found that it can significantly alleviate the myocardial damage caused by MIRI in vivo and exert effective therapeutic effects. Conclusions This research has developed a PMVs camouflaged PLGA nanoparticles, which can carry microRNA inhibitors (PMVs@PLGA-miRNA complexes), which can be targeted and efficiently transfected into cardiomyocytes, and play an important role in the treatment of MIRI. Our results suggest a novel biological delivery system that targets M​​IRI.

scholarly journals Sp1 Targeted PARP1 Inhibition Protects Cardiomyocytes From Myocardial Ischemia–Reperfusion Injury via Downregulation of Autophagy

2021 ◽  
Vol 9 ◽  
Author(s):  
Yifeng Xu ◽  
Boqian Wang ◽  
Xiaoxiao Liu ◽  
Yunfei Deng ◽  
Yanqi Zhu ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Reperfusion Injury ◽  
Target Gene ◽  
Ischemia Reperfusion Injury ◽  
Therapeutic Potential ◽  
Ischemia Reperfusion ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Myocardial ischemia–reperfusion injury (MIRI), characterized by post-ischemic cardiomyocytes death and reperfusion myocardial damage, is a lethal yet unresolved complication in the treatment of acute myocardial infarction (AMI). Previous studies have demonstrated that poly(ADP-ribose) polymerase-1 (PARP1) participates in the progression of various cardiovascular diseases, and various reports have proved that PARP1 can be a therapeutic target in these diseases, but whether it plays a role in MIRI is still unknown. Therefore, in this study, we aimed to explore the role and mechanism of PARP1 in the development of MIRI. Firstly, we demonstrated that PARP1 was activated during MIRI-induced myocardial autophagy in vitro. Moreover, PARP1 inhibition protected cardiomyocytes from MIRI through the inhibition of autophagy. Next, we discovered that specificity protein1 (Sp1), as a transcription factor of PARP1, regulates its target gene PARP1 through binding to its target gene promoter during transcription. Furthermore, silencing Sp1 protected cardiomyocytes from MIRI via the inhibition of PARP1. Finally, the functions and mechanisms of PARP1 in the development of MIRI were also verified in vivo with SD rats model. Based on these findings, we concluded that PARP1 inhibition protects cardiomyocytes from MIRI through the inhibition of autophagy, which is targeted by Sp1 suppression. Therefore, the utilization of PARP1 exhibits great therapeutic potential for MIRI treatment in future.

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