Recent Advance on Drug Therapy Related to Myocardial Ischemia Reperfusion Injury

Myocardial ischemia reperfusion injury (MIRI) means complete or partial artery obstruction of coronary artery, and ischemic myocardium will be recirculating in a period of time. Although the ischemic myocardium can be restored to normal perfusion, its tissue damage will instead be progressive. An aggravated pathological process. MIRI is a complex entity where many inflammatory mediators play different roles, both to enhance myocardial infarction-derived damage and to heal injury. Therefore, the research and development of drugs for the prevention and treatment of this period has also become the focus. This article first studied pathophysiology of MIRI, and reviewed the research progress of MIRI-related drugs. Research results show that: MIRI is inevitable for myocardial ischemia, with the possible to double damage via the ischemic condition. Therefore, it is a serious complication and one of the most popular diseases in the world. It has always been difficult to find an effective treatment for this disease, because it is difficult to explore the inflammation behind its pathophysiology.

Simvastatin Improves Myocardial Ischemia Reperfusion Injury through KLF-Regulated Alleviation of Inflammation

Objective. To clarify the protective effect of simvastatin on myocardial ischemia reperfusion injury (MIRI) and the underlying mechanism. Materials and Methods. The MIRI model in rats was firstly constructed. Twenty-four male rats were randomly assigned into the sham group, ischemia-reperfusion (I/R) group, and simvastatin group, with 8 rats in each group. Contents of superoxide dismutase (SOD) and malondialdehyde (MDA), as well as serum levels of CK and inflammatory factors, in rats were determined by the enzyme-linked immunosorbent assay (ELISA). Lactate dehydrogenase (LDH) activity in the three groups was examined. Through flow cytometry and Cell Counting Kit-8 (CCK-8) assay, apoptosis and viability in each group were detected, respectively. Relative levels of HMGB1, Kruppel-like factor 2 (KLF2), eNOS, and thrombomodulin (TM) were finally determined. Results. Simvastatin treatment markedly enhanced SOD activity and reduced contents of MDA, LDH, and creatine kinase (CK) in MIRI rats. The increased apoptosis and decreased viability following MIRI were partially reversed by simvastatin treatment. Besides, MIRI resulted in the upregulation of inflammatory factors and chemokines. Their elevations were abolished by simvastatin. In MIRI rats, simvastatin upregulated KLF2 and p-eNOS. Conclusions. Simvastatin protects inflammatory response at post-MIRI through upregulating KLF2, thus improving cardiac function.

Sodium-Glucose Co-transporter-2 Inhibitor of Dapagliflozin Attenuates Myocardial Ischemia/Reperfusion Injury by Limiting NLRP3 Inflammasome Activation and Modulating Autophagy

Background: The sodium-glucose co-transporter-2 (SGLT-2) inhibitor dapagliflozin improves cardiovascular outcomes in patients with type 2 diabetes in a manner that is partially independent of its hypoglycemic effect. These observations suggest that it may exert a cardioprotective effect by another mechanism. This study explored the effects of dapagliflozin on myocardial ischemia/reperfusion injury in a mouse model.Materials and Methods: For the in vivo I/R studies, mice received 40 mg/kg/d dapagliflozin, starting 7 days before I/R. Evans Blue/TTC double-staining was used to determine the infarct size. Serum levels of cTnI, CK-MB, and LDH were measured. Inflammation, autophagy protein expression, and caspase-1 activity changes were measured at the protein level. Primary cardiomyocytes were used to investigate the direct effect of dapagliflozin on cardiomyocytes and to verify whether they have the same effect as observed in in vivo experiments.Result: A high dose of dapagliflozin significantly reduced infarct size and decreased the serum levels of cTnI, CK-MB, and LDH. Dapagliflozin also reduced serum levels of IL-1β, reduced expression of myocardial inflammation-related proteins, and inhibited cardiac caspase-1 activity. The treatment restored autophagy flux and promoted the degradation of autophagosomes. Relief of inflammation relied on autophagosome phagocytosis of NLRP3 and autophagosome clearance after lysosome improvement. 10 μM dapagliflozin reduced intracellular Ca2+ and Na+ in primary cardiomyocytes, and increasing NHE1 and NCX expression mitigated dapagliflozin effects on autophagy.Conclusion: Dapagliflozin protects against myocardial ischemia/reperfusion injury independently of its hypoglycemic effect. High-dose dapagliflozin pretreatment might limit NLRP3 inflammasome activation and mediate its selective autophagy. Dapagliflozin directly acts on cardiomyocytes through NHE1/NCX.

MicroRNA-489 Promotes the Apoptosis of Cardiac Muscle Cells in Myocardial Ischemia-Reperfusion Based on Smart Healthcare

With the development of information technology, the concept of smart healthcare has gradually come to the fore. Smart healthcare uses a new generation of information technologies, such as the Internet of Things (loT), big data, cloud computing, and artificial intelligence, to transform the traditional medical system in an all-around way, making healthcare more efficient, more convenient, and more personalized. miRNAs can regulate the proliferation, differentiation, and apoptosis of human cells. Relevant studies have also shown that miRNAs may play a key role in the occurrence and development of myocardial ischemia-reperfusion injury (MIRI). This study aims to explore the effects of miR-489 in MIRI. In this study, miR-489 expression in a myocardial ischemia-reperfusion animal model and H9C2 cells induced by H/R was detected by qRT-PCR. The release of lactate dehydrogenase (LDH) and the activity of creatine kinase (CK) was detected after miR-489 knockdown in H9C2 cells induced by H/R. The apoptosis of H9C2 cells and animal models were determined by ELISA. The relationship between miR-489 and SPIN1 was verified by a double fluorescence reporter enzyme assay. The expression of the PI3K/AKT pathway-related proteins was detected by Western blot. Experimental results showed that miR-489 was highly expressed in cardiac muscle cells of the animal model and in H9C2 cells induced by H/R of the myocardial infarction group, which was positively associated with the apoptosis of cardiac muscle cells with ischemia-reperfusion. miR-489 knockdown can reduce the apoptosis of cardiac muscle cells caused by ischemia-reperfusion. In downstream targeting studies, it was found that miR-489 promotes the apoptosis of cardiac muscle cells after ischemia-reperfusion by targeting the inhibition of the SPIN1-mediated PI3K/AKT pathway. In conclusion, high expression of miR-489 is associated with increased apoptosis of cardiac muscle cells after ischemia-reperfusion, which can promote the apoptosis after ischemia-reperfusion by targeting the inhibition of the SPIN1-mediated PI3K/AKT pathway. Therefore, miR-489 can be one of the potential therapeutic targets for reducing the apoptosis of cardiac muscle cells after ischemia-reperfusion.

Endoplasmic Reticulum Stress/Ca2+-Calmodulin-Dependent Protein Kinase/Signal Transducer and Activator of Transcription 3 Pathway Plays a Role in the Regulation of Cellular Zinc Deficiency in Myocardial Ischemia/Reperfusion Injury

Zinc homeostasis has been known to play a role in myocardial ischemia/reperfusion (I/R) injury, but the precise molecular mechanisms regulating the expression of ZIP transporters during reperfusion are still unclear. The aim of this study was to determine whether ER Stress/CaMKII/STAT3 pathway plays a role in the regulation of cellular zinc homeostasis. Zinc deficiency increased mRNA and protein expressions of the ER stress relevant markers Chop and Bip, and STAT3 phosphorylation in H9c2 or HL-1 cells, an effect that was abolished by ZnCl2. ER calcium concentration [(Ca2+)ER] was decreased and cytosolic calcium concentration [(Ca2+)I] was increased at the condition of normoxia or ischemia/reperfusion, indicating that zinc deficiency triggers ER stress and Ca2+ leak. Further studies showed that upregulation of STAT3 phosphorylation was reversed by Ca2+ chelator, indicating that intracellular Ca2+ is important for zinc deficiency-induced STAT3 activation. In support, zinc deficiency enhanced ryanodine receptors (RyR), a channel in the ER that mediate Ca2+ release, and Ca2+-calmodulin-dependent protein kinase (CaMKII) phosphorylation, implying that zinc deficiency provoked Ca2+ leak from ER via RyR and p-CaMKII is involved in STAT3 activation. Moreover, inhibition of STAT3 activation blocked zinc deficiency induced ZIP9 expression, and resulted in increased Zn2+ loss in cardiomyocytes, further confirming that STAT3 activation during reperfusion promotes the expression of ZIP9 zinc transporter to correct the imbalance in zinc homeostasis. In addition, suppressed STAT3 activation aggravated reperfusion injury. These data suggest that the ER Stress/CaMKII/STAT3 axis may be an endogenous protective mechanism, which increases the resistance of the heart to I/R.

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

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.