RESUMEN
Myocardial ischemia-reperfusion (I/R) injury exacerbates cellular damage upon restoring blood flow to ischemic cardiac tissue, causing oxidative stress, inflammation, and apoptosis. This study investigates Nicotinamide Riboside (NR), a precursor of nicotinamide adenine dinucleotide (NAD+), for its cardioprotective effects. Administering NR to mice before I/R injury and evaluating heart function via echocardiography showed that NR significantly improved heart function, increased left ventricular ejection fraction (LVEF) and fractional shortening (FS), and reduced left ventricular end-diastolic (LVDd) and end-systolic diameters (LVSd). NR also restored E/A and E/e' ratios. It reduced cardiomyocyte apoptosis both in vivo and in vitro, inhibiting elevated caspase-3 activity and returning Bax protein levels to normal. In vitro, NR reduced the apoptotic rate in hydrogen peroxide (H2O2)-treated HL-1 cells from 30% to 10%. Mechanistically, NR modulated the SIRT3/mtROS/JNK pathway, reversing H2O2-induced SIRT3 downregulation, reducing mitochondrial reactive oxygen species (mtROS), and inhibiting JNK activation. Using SIRT3-knockout (SIRT3-KO) mice, we confirmed that NR's cardioprotective effects depend on SIRT3. Echocardiography showed that NR's benefits were abrogated in SIRT3-KO mice. In conclusion, NR provides significant cardioprotection against myocardial I/R injury by enhancing NAD+ levels and modulating the SIRT3/mtROS/JNK pathway, suggesting its potential as a novel therapeutic agent for ischemic heart diseases, meriting further clinical research.
Asunto(s)
Apoptosis , Ratones Noqueados , Daño por Reperfusión Miocárdica , Niacinamida , Compuestos de Piridinio , Especies Reactivas de Oxígeno , Sirtuina 3 , Animales , Sirtuina 3/metabolismo , Sirtuina 3/genética , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Niacinamida/análogos & derivados , Niacinamida/farmacología , Niacinamida/uso terapéutico , Ratones , Compuestos de Piridinio/farmacología , Compuestos de Piridinio/administración & dosificación , Especies Reactivas de Oxígeno/metabolismo , Apoptosis/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Estrés Oxidativo/efectos de los fármacos , Humanos , Cardiotónicos/farmacología , Cardiotónicos/uso terapéutico , Modelos Animales de Enfermedad , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Ratones Endogámicos C57BL , Transducción de Señal/efectos de los fármacosRESUMEN
Myocardial ischaemia reperfusion injury (IRI) occurring from acute coronary artery disease or cardiac surgical interventions such as bypass surgery can result in myocardial dysfunction, presenting as, myocardial "stunning", arrhythmias, infarction, and adverse cardiac remodelling, and may lead to both a systemic and a localised inflammatory response. This localised cardiac inflammatory response is regulated through the nucleotide-binding oligomerisation domain (NACHT), leucine-rich repeat (LRR)-containing protein family pyrin domain (PYD)-3 (NLRP3) inflammasome, a multimeric structure whose components are present within both cardiomyocytes and in cardiac fibroblasts. The NLRP3 inflammasome is activated via numerous danger signals produced by IRI and is central to the resultant innate immune response. Inhibition of this inherent inflammatory response has been shown to protect the myocardium and stop the occurrence of the systemic inflammatory response syndrome following the re-establishment of cardiac circulation. Therapies to prevent NLRP3 inflammasome formation in the clinic are currently lacking, and therefore, new pharmacotherapies are required. This review will highlight the role of the NLRP3 inflammasome within the myocardium during IRI and will examine the therapeutic value of inflammasome inhibition with particular attention to carbon monoxide, nitric oxide, and hydrogen sulphide as potential pharmacological inhibitors of NLRP3 inflammasome activation.
Asunto(s)
Monóxido de Carbono , Sulfuro de Hidrógeno , Inflamasomas , Infarto del Miocardio , Proteína con Dominio Pirina 3 de la Familia NLR , Óxido Nítrico , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Humanos , Sulfuro de Hidrógeno/metabolismo , Sulfuro de Hidrógeno/farmacología , Inflamasomas/metabolismo , Óxido Nítrico/metabolismo , Infarto del Miocardio/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/patología , Animales , Monóxido de Carbono/metabolismo , Gasotransmisores/metabolismo , Cardiotónicos/farmacología , Cardiotónicos/uso terapéutico , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/prevención & control , Daño por Reperfusión Miocárdica/patologíaRESUMEN
Fucoxanthin (Fx), a xanthophyll carotenoid abundant in brown algae, possesses several biological functions, such as antioxidant, anti-inflammatory, and cardiac-protective activities. However, the role of Fx in myocardial ischemia/reperfusion (MI/R) is still unclear. Thus, the aim of this study was to investigate the effect of Fx on MI/R-induced injury and explore the underlying mechanisms. Our results showed that in vitro, Fx treatment significantly suppressed inflammatory response, oxidative stress, and apoptosis in rat cardiomyocytes exposed to hypoxia/reoxygenation (H/R). In addition, Fx led to increased phosphorylation of AMPK, AKT, and GSK-3ß, and enhanced activation of Nrf2 in cardiomyocytes under H/R conditions. Notably, pretreatment with Compound C (AMPK inhibitor), partially reduced the beneficial effects of Fx in cardiomyocytes exposed to H/R. In vivo, Fx ameliorated myocardial damage, inhibited inflammatory response, oxidative stress, and apoptosis, and activated the AMPK/GSK-3ß/Nrf2 signaling in myocardial tissues in MI/R rat model. Taken together, these findings indicated that Fx attenuates MI/R-induced injury by inhibiting oxidative stress, inflammatory response, and apoptosis. The AMPK/GSK-3ß/Nrf2 pathway is involved in the cardioprotective effect of Fx in MI/R injury. Thus, Fx may be a promising drug for the treatment of MI/R.
Asunto(s)
Proteínas Quinasas Activadas por AMP , Apoptosis , Glucógeno Sintasa Quinasa 3 beta , Daño por Reperfusión Miocárdica , Miocitos Cardíacos , Factor 2 Relacionado con NF-E2 , Estrés Oxidativo , Transducción de Señal , Xantófilas , Animales , Ratas , Proteínas Quinasas Activadas por AMP/efectos de los fármacos , Proteínas Quinasas Activadas por AMP/metabolismo , Apoptosis/efectos de los fármacos , Glucógeno Sintasa Quinasa 3 beta/efectos de los fármacos , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/patología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Factor 2 Relacionado con NF-E2/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Xantófilas/farmacología , Xantófilas/químicaRESUMEN
While 3-N-butylphthalide (NBP) has demonstrated notable cardioprotective effects, its precise role in mitigating myocardial arrhythmia following ischemia/reperfusion (IR) injury in diabetes remains unclear. This study aimed to explore the potential mechanisms through which NBP mitigates reperfusion-induced myocardial arrhythmia in diabetic rats, with a particular focus on mitochondrial function and biogenesis, endoplasmic reticulum (ER) stress, and oxidative/inflammatory responses. Sixty Sprague-Dawley rats were divided into non-diabetic and diabetic groups, subjected to in-vivo myocardial IR injury, and treated with NBP (100 mg/kg, intraperitoneally) through different modalities: preconditioning, postconditioning, or a combination of both. Electrocardiography (ECG) was employed to assess the incidence and severity of arrhythmia. Fluorometric, Western blotting and ELISA analyses were utilized to measure the mitochondrial, ER stress, and cellular outcomes. Treatment of non-diabetic rats with NBP in preconditioned, postconditioned, and combined approaches significantly reduced cardiotroponin-I and the frequency and severity of arrhythmias induced by IR injury. However, only the combined preconditioning plus postconditioning approach of NBP had protective and antiarrhythmic effects in diabetic rats, in an additive manner. Moreover, the NBP combined approach improved mitochondrial function and upregulated the expression of PGC-1?, Sirt1, and glutathione while concurrently downregulating ER stress and oxidative and pro-inflammatory-related proteins in diabetic rats. In conclusion, the combined approach of NBP treatment was effective in mitigating myocardial arrhythmia in diabetic rats. This approach coordinates interactions within the mitochondria-endoplasmic reticulum network and inhibits oxidative and inflammatory mediators, offering a promising strategy for managing myocardial arrhythmia in diabetic patients. Key words: Myocardial Infarction, Mitochondria, Arrhythmia, Reperfusion, Diabetes, Ischemia.
Asunto(s)
Arritmias Cardíacas , Benzofuranos , Diabetes Mellitus Experimental , Estrés del Retículo Endoplásmico , Daño por Reperfusión Miocárdica , Estrés Oxidativo , Ratas Sprague-Dawley , Animales , Estrés Oxidativo/efectos de los fármacos , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/prevención & control , Benzofuranos/farmacología , Benzofuranos/uso terapéutico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/complicaciones , Masculino , Arritmias Cardíacas/etiología , Arritmias Cardíacas/prevención & control , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/tratamiento farmacológico , Ratas , Estrés del Retículo Endoplásmico/efectos de los fármacos , Antiarrítmicos/farmacología , Antiarrítmicos/uso terapéutico , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/efectos de los fármacos , Inflamación/metabolismo , Inflamación/tratamiento farmacológicoRESUMEN
Targeting Meis1 and Hoxb13 transcriptional activity could be a viable therapeutic strategy for heart regeneration. In this study, we performd an in silico screening to identify FDA-approved drugs that can inhibit Meis1 and Hoxb13 transcriptional activity based on the resolved crystal structure of Meis1 and Hoxb13 bound to DNA. Paromomycin (Paro) and neomycin (Neo) induced proliferation of neonatal rat ventricular myocytes in vitro and displayed dose-dependent inhibition of Meis1 and Hoxb13 transcriptional activity by luciferase assay and disruption of DNA binding by electromobility shift assay. X-ray crystal structure revealed that both Paro and Neo bind to Meis1 near the Hoxb13-interacting domain. Administration of Paro-Neo combination in adult mice and in pigs after cardiac ischemia/reperfusion injury induced cardiomyocyte proliferation, improved left ventricular systolic function and decreased scar formation. Collectively, we identified FDA-approved drugs with therapeutic potential for induction of heart regeneration in mammals.
Asunto(s)
Proliferación Celular , Proteínas de Homeodominio , Proteína 1 del Sitio de Integración Viral Ecotrópica Mieloide , Miocitos Cardíacos , Regeneración , Animales , Regeneración/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Proteínas de Homeodominio/metabolismo , Proteínas de Homeodominio/genética , Proliferación Celular/efectos de los fármacos , Proteína 1 del Sitio de Integración Viral Ecotrópica Mieloide/metabolismo , Proteína 1 del Sitio de Integración Viral Ecotrópica Mieloide/genética , Neomicina/farmacología , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Modelos Animales de Enfermedad , Aprobación de Drogas , Ratones , Función Ventricular Izquierda/efectos de los fármacos , United States Food and Drug Administration , Ratas , Estados Unidos , Cristalografía por Rayos X , Masculino , Ratones Endogámicos C57BL , Porcinos , Células Cultivadas , Transcripción Genética/efectos de los fármacosRESUMEN
Effective treatment of myocardial ischemia-reperfusion (MIR) injury remains an unmet clinical need. Cardiomyocyte apoptosis is common at this stage and poses a significant risk. Corylin, a flavonoid compound extracted from Psoralea corylifolia L., has been shown to have anti-inflammatory, anticancer, and antiatherosclerotic properties. However, whether and how corylin affects MIR injury remain unclear. In this study, we explored the mechanism of corylin as a potent therapeutic agent for MI/R injury, using a left anterior descending (LAD) coronary artery ligation and oxygen-glucose deprivation and reperfusion (OGD/R) model in vivo and in vitro. TUNEL, Annexin-V/PI double staining,Ki67 immunohistochemistry, western blot analysis, and immunofluorescence were used to validate cell apoptosis level and Raf-1/ASK1 complex activity. The interaction between corylin and Raf-1/ASK1 complex was detected using molecular docking, corylin-Raf-1 binding assays, and coimmunoprecipitation (Co-IP). Moreover, TTC staining, echocardiography, HE staining, Masson trichrome staining and serological testing were performed to assess the cardioprotective effects of corylin in vivo. These findings showed that corylin reduces MIR injury-induced cardiomyocyte apoptosis and improves cardiac function. Mechanistically, corylin can interact with Raf-1 and promote the formation of the Raf-1/ASK1 complex, thus inhibiting cardiomyocyte apoptosis. In conclusion, our results demonstrate that corylin ameliorated cardiac dysfunction after MIR injury by reducing myocardial apoptosis.
Asunto(s)
Apoptosis , MAP Quinasa Quinasa Quinasa 5 , Daño por Reperfusión Miocárdica , Miocitos Cardíacos , Proteínas Proto-Oncogénicas c-raf , Apoptosis/efectos de los fármacos , Animales , Proteínas Proto-Oncogénicas c-raf/metabolismo , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Masculino , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , MAP Quinasa Quinasa Quinasa 5/metabolismo , Flavonoides/farmacología , Flavonoides/uso terapéutico , Ratones Endogámicos C57BL , Ratones , Humanos , Psoralea/química , Modelos Animales de EnfermedadRESUMEN
BACKGROUND: Although blood flow is restored after treatment of myocardial infarction (MI), myocardial ischemia and reperfusion (I/R) can cause cardiac injury, which is a leading cause of heart failure. Gastrodin (GAS) exerts protective effects against brain, heart, and kidney I/R. However, its pharmacological mechanism in myocardial I/R injury (MIRI) remains unclear. PURPOSE: GAS regulates autophagy in various diseases, such as acute hepatitis, vascular dementia, and stroke. We hypothesized that GAS could repair mitochondrial damage and regulate autophagy to protect against MIRI. STUDY DESIGN: Male C57BL/6 mice and H9C2 cells were subjected to I/R and hypoxia-reoxygenation (H/R) injury after GAS administration, respectively, to assess the impact of GAS on cardiomyocyte phenotypes, heart, and mitochondrial structure and function. The effect of GAS on cardiac function and mitochondrial structure in patients undergoing cardiac surgery has been observed in clinical practice. METHODS: The effects of GAS on cardiac structure and function, mitochondrial structure, and expression of related molecules in an animal model of MIRI were evaluated using immunohistochemical staining, enzyme-linked immunosorbent assay (ELISA), transmission electron microscopy, western blotting, and gene sequencing. Its effects on the morphological, molecular, and functional phenotypes of cardiomyocytes undergoing H/R were observed using immunohistochemical staining, real-time quantitative PCR, and western blotting. RESULTS: GAS significantly reduces myocardial infarct size and improves cardiac function in MIRI mice in animal models and increases cardiomyocyte viability and reduces cardiomyocyte damage in cellular models. In clinical practice, myocardial injury was alleviated with better cardiac function in patients undergoing cardiac surgery after the application of GAS; improvements in mitochondria and autophagy activation were also observed. GAS primarily exerts cardioprotective effects through activation of the PINK1/Parkin pathway, which promotes mitochondrial autophagy to clear damaged mitochondria. CONCLUSION: GAS can promote mitophagy and preserve mitochondria through PINK1/Parkin, thus indicating its tremendous potential as an effective perioperative myocardial protective agent.
Asunto(s)
Alcoholes Bencílicos , Glucósidos , Ratones Endogámicos C57BL , Mitofagia , Daño por Reperfusión Miocárdica , Miocitos Cardíacos , Proteínas Quinasas , Ubiquitina-Proteína Ligasas , Animales , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Alcoholes Bencílicos/farmacología , Glucósidos/farmacología , Mitofagia/efectos de los fármacos , Masculino , Ubiquitina-Proteína Ligasas/metabolismo , Ratones , Miocitos Cardíacos/efectos de los fármacos , Proteínas Quinasas/metabolismo , Línea Celular , Modelos Animales de Enfermedad , Humanos , Miocardio/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Cardiotónicos/farmacologíaRESUMEN
This study aimed to investigate the cardioprotective effect of quinacrine in an in vivo model of myocardial ischemia/reperfusion injury. A 30-min regional myocardial ischemia followed by a 2-h reperfusion was modeled in anesthetized Wistar rats. Starting at the last minute of ischemia and during the first 9 min of reperfusion the rats in the control (n=8) and experimental (n=9) groups were injected with 0.9% NaCl and quinacrine solution (5 mg/kg), respectively. The area at risk and infarct size were evaluated by "double staining" with Evans blue and triphenyltetrazolium chloride. To assess vascular permeability in the area at risk zone, indocyanine green (ICG) and thioflavin S (ThS) were injected intravenously at the 90th and 120th minutes of reperfusion, respectively, to assess the no-reflow zone. The images of ICG and ThS fluorescence in transverse sections of rat hearts were obtained using a FLUM multispectral fluorescence organoscope. HR tended to decrease by 13% after intravenous administration of quinacrine and then recovered within 50 min. Quinacrine reduced the size of the necrotic zone (p=0.01), vascular permeability in the necrosis region, and the no-reflow area (p=0.027); at the same time, the area at risk did not significantly differ between the groups. Intravenous administration of quinacrine at the beginning of reperfusion of the rat myocardium reduces no-reflow phenomenon and infarct size.
Asunto(s)
Cardiotónicos , Daño por Reperfusión Miocárdica , Quinacrina , Ratas Wistar , Animales , Quinacrina/farmacología , Quinacrina/uso terapéutico , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/patología , Ratas , Masculino , Cardiotónicos/farmacología , Cardiotónicos/uso terapéutico , Modelos Animales de Enfermedad , Permeabilidad Capilar/efectos de los fármacos , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/patología , Miocardio/patologíaRESUMEN
Brown adipose tissue (BAT) plays a critical role in regulating cardiovascular homeostasis through the secretion of adipokines, such as fibroblast growth factor 21 (FGF21). Dexmedetomidine (DEX) is a selective α2-adrenergic receptor agonist with a protection against myocardial ischemia/reperfusion injury (MI/RI). It remains largely unknown whether or not BAT-derived FGF21 is involved in DEX-induced cardioprotection in the context of MI/RI. Herein, we demonstrated that DEX alleviated MI/RI and improved heart function through promoting the release of FGF21 from interscapular BAT (iBAT). Surgical iBAT depletion or supplementation with a FGF21 neutralizing antibody attenuated the beneficial effects of DEX. AMPK/PGC1α signaling-induced fibroblast growth factor 21 (FGF21) release in brown adipocytes is required for DEX-mediated cardioprotection since blockade of the AMPK/PGC1α axis weakened the salutary effects of DEX. Co-culture experiments showed that DEX-induced FGF21 from brown adipocytes increased the resistance of cardiomyocytes to hypoxia/reoxygenation (H/R) injury via modulating the Keap1/Nrf2 pathway. Our results provided robust evidence that the BAT-cardiomyocyte interaction is required for DEX cardioprotection, and revealed an endocrine role of BAT in DEX-mediating protection of hearts against MIRI.
Asunto(s)
Tejido Adiposo Pardo , Dexmedetomidina , Factores de Crecimiento de Fibroblastos , Daño por Reperfusión Miocárdica , Miocitos Cardíacos , Dexmedetomidina/farmacología , Animales , Factores de Crecimiento de Fibroblastos/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/prevención & control , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Pardo/efectos de los fármacos , Ratones , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Masculino , Cardiotónicos/farmacología , Ratones Endogámicos C57BL , Transducción de Señal/efectos de los fármacos , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Adipocitos Marrones/metabolismo , Adipocitos Marrones/efectos de los fármacosRESUMEN
In myocardial infarction, ischemia-reperfusion injury (IRI) poses a significant challenge due to a lack of effective treatments. Bilirubin, a natural compound known for its anti-inflammatory and antioxidant properties, has been identified as a potential therapeutic agent for IRI. Currently, there are no reports about proteomic studies related to IRI and bilirubin treatment. In this study, we explored the effects of bilirubin nanoparticles in a rat model of myocardial IRI. A total of 3616 protein groups comprising 76,681 distinct peptides were identified using LC-MS/MS, where we distinguished two kinds of protein groups: those showing increased expression in IRI and decreased expression in IRI with bilirubin treatment, and vice versa, accounting for 202 and 35 proteins, respectively. Our proteomic analysis identified significant upregulation in the Wnt and insulin signaling pathways and increased Golgi markers, indicating their role in mediating bilirubin nanoparticle's protective effects. This research contributes to the proteomic understanding of myocardial IRI and suggests bilirubin nanoparticles as a promising strategy for cardiac protection, warranting further investigation in human models.
Asunto(s)
Bilirrubina , Daño por Reperfusión Miocárdica , Nanopartículas , Proteómica , Espectrometría de Masas en Tándem , Animales , Bilirrubina/farmacología , Nanopartículas/química , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/metabolismo , Proteómica/métodos , Ratas , Masculino , Ratas Sprague-Dawley , Cromatografía Liquida , Modelos Animales de Enfermedad , Vía de Señalización Wnt/efectos de los fármacosRESUMEN
Gastric precancerous lesion (GPL) is a crucial stage in the development of gastric cancer, characterized by incomplete intestinal epithelial chemotaxis and heterogeneous hyperplasia with high malignant potential. Early intervention in GPL is vital for preventing gastric cancer. Additionally, there are shared risk factors and pathogenesis between tumors and coronary heart disease (CHD), with an increasing number of tumor patients GPL complicated with CHD due to improved survival rates. Reperfusion therapy in CHD can result in myocardial ischemia-reperfusion injury (MIRI). Traditional Chinese medicine (TCM) has demonstrated unique advantages in treating GPL and MIRI by promoting blood circulation and removing blood stasis. Panax ginseng total saponin (PNS), a component of TCM known for its blood circulation benefits, has shown positive effects in inhibiting tumor growth and improving myocardial ischemia. This study utilized a GPL-MIRI mouse model to investigate the effects of PNS in treatment. Results indicated that PNS significantly improved typical GPL lesions in mice, such as incomplete intestinal epithelialization and heteroplasia, and also reduced myocardial infarction. At the molecular level, PNS exhibited a bidirectional regulatory role in the GPL-MIRI model. It enhanced the autophagic process in gastric mucosal cells by inhibiting the PI3K/Akt/mTOR signaling pathway, while suppressed excessive autophagy in cardiomyocytes. These findings offer new insights and treatment strategies for managing GPL and MIRI using the TCM compound PNS.
Asunto(s)
Autofagia , Daño por Reperfusión Miocárdica , Panax notoginseng , Saponinas , Transducción de Señal , Neoplasias Gástricas , Animales , Masculino , Ratones , Autofagia/efectos de los fármacos , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/metabolismo , Panax notoginseng/química , Fosfatidilinositol 3-Quinasas/metabolismo , Lesiones Precancerosas/tratamiento farmacológico , Lesiones Precancerosas/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Saponinas/farmacología , Saponinas/uso terapéutico , Transducción de Señal/efectos de los fármacos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Neoplasias Gástricas/metabolismo , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
BACKGROUND: Ischemia reperfusion (IR) causes impaired myocardial function, and autophagy activation ameliorates myocardial IR injury. Isoliquiritigenin (ISO) has been found to protect myocardial tissues via AMPK, with exerting anti-tumor property through autophagy activation. This study aims to investigate ISO capacity to attenuate myocardial IR through autophagy activation mediated by AMPK/mTOR/ULK1 signaling. METHODS: ISO effects were explored by SD rats and H9c2 cells. IR rats and IR-induced H9c2 cell models were established by ligating left anterior descending (LAD) coronary artery and hypoxia/re-oxygenation, respectively, followed by low, medium and high dosages of ISO intervention (Rats: 10, 20, and 40 mg/kg; H9c2 cells: 1, 10, and 100 µmol/L). Myocardial tissue injury in rats was assessed by myocardial function-related index, HE staining, Masson trichrome staining, TTC staining, and ELISA. Autophagy of H9c2 cells was detected by transmission electron microscopy (TEM) and immunofluorescence. Autophagy-related and AMPK/mTOR/ULK1 pathway-related protein expressions were detected with western blot. RESULTS: ISO treatment caused myocardial function improvement, and inhibition of myocardial inflammatory infiltration, fibrosis, infarct area, oxidative stress, CK-MB, cTnI, and cTnT expression in IR rats. In IR-modeled H9c2 cells, ISO treatment lowered apoptosis rate and activated autophagy and LC3 fluorescence expression. In vivo and in vitro, ISO intervention exhibited enhanced Beclin1, LC3II/LC3I, and p-AMPK/AMPK levels, whereas inhibited P62, p-mTOR/mTOR and p-ULK1(S757)/ULK1 protein expression, activating autophagy and protecting myocardial tissues from IR injury. CONCLUSION: ISO treatment may induce autophagy by regulating AMPK/mTOR/ULK1 signaling, thereby improving myocardial IR injury, as a potential candidate for treatment of myocardial IR injury.
Asunto(s)
Proteínas Quinasas Activadas por AMP , Homólogo de la Proteína 1 Relacionada con la Autofagia , Autofagia , Chalconas , Daño por Reperfusión Miocárdica , Miocitos Cardíacos , Ratas Sprague-Dawley , Transducción de Señal , Serina-Treonina Quinasas TOR , Animales , Masculino , Ratas , Proteínas Quinasas Activadas por AMP/metabolismo , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Homólogo de la Proteína 1 Relacionada con la Autofagia/metabolismo , Línea Celular , Chalconas/farmacología , Modelos Animales de Enfermedad , Fibrosis , Infarto del Miocardio/patología , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , Infarto del Miocardio/fisiopatología , Infarto del Miocardio/enzimología , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/fisiopatología , Daño por Reperfusión Miocárdica/enzimología , Daño por Reperfusión Miocárdica/prevención & control , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Miocitos Cardíacos/enzimología , Miocitos Cardíacos/metabolismo , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
BACKGROUND: Microvascular dysfunction (MVD) is common in patients with myocardial infarction receiving reperfusion therapy and is associated with adverse cardiac prognosis. Accumulating evidence suggests a protective role of Shexiang Tongxin dropping pill (STDP) in MVD. However, the specific effects and the underlying mechanisms of STDP in the context of MVD after myocardial ischemia-reperfusion (IR) remains unclear. AIMS: We aimed to elucidate the role of STDP in MVD induced by IR and the potential mechanisms involved. METHODS: Mice were orally administered with STDP or normal saline for 5 days before receiving myocardial IR. Cardiac function and microvascular obstruction was measured. Proteomics and single-cell RNA sequencing was performed on mouse hearts. In vitro hyoxia/reoxygenation model was established on mouse cardiac microvascular endothelial cells (MCMECs). RESULTS: STDP improved cardiac function and decreased microvascular obstruction (MVO) in mice after myocardial IR. Proteomics identified ALOX12 as an important target of STDP. Single-cell RNA sequencing further revealed that downregulation of ALOX12 by STDP mainly occurred in endothelial cells. The involvement of ALOX12 in the effect of STDP on MVO was validated by manipulating ALOX12 via endothelial-specific adeno-associated virus transfection in vivo and in vitro. In vivo, overexpression of ALOX12 increased whereas knockdown of ALOX12 decreased MVO and thrombus formation. STDP treatment alleviated the detrimental effects of overexpression of ALOX12. In vitro, overexpression of ALOX12 increased endothelial cell inflammation and platelet adhesion to endothelial cells, which was abolished by STDP treatment. CONCLUSION: Our findings suggest that STDP alleviates MVO after IR, with ALOX12 playing a crucial role.
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Araquidonato 12-Lipooxigenasa , Regulación hacia Abajo , Medicamentos Herbarios Chinos , Ratones Endogámicos C57BL , Daño por Reperfusión Miocárdica , Animales , Ratones , Medicamentos Herbarios Chinos/farmacología , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/genética , Regulación hacia Abajo/efectos de los fármacos , Masculino , Araquidonato 12-Lipooxigenasa/metabolismo , Araquidonato 12-Lipooxigenasa/genética , Microvasos/efectos de los fármacos , Microvasos/metabolismo , Modelos Animales de EnfermedadRESUMEN
After myocardial ischemia/reperfusion injury (MI/RI), endothelial cell injury causes impaired angiogenesis and obstruction of microcirculation, resulting in an inflammatory outburst that exacerbates the damage. Therefore, synergistic blood vessel repair and inflammation inhibition are effective therapeutic strategies. In this study, we developed a platelet membrane (PM)-encapsulated baicalin nanocrystalline (BA NC) nanoplatform with a high drug load, BA NC@PM, which co-target to endothelial cells and macrophages through the transmembrane proteins of the PM to promote angiogenesis and achieve anti-inflammatory effects. In vitro cell scratch assays and transwell assay manifested that BA NC@PM could promote endothelial cell migration, as well as increase mRNA expression of CD31 and VEGF in the heart after treatment of MI/RI mice, suggesting its favorable vascular repair function. In addition, the preparation significantly reduced the expression of pro-inflammatory factors and increased the expression of anti-inflammatory factors in plasma, promoting the polarization of macrophages. Our study highlights a strategy for enhancing the treatment of MI/RI by promoting angiogenesis and regulating macrophage polarization via the biomimetic BA NC@PM nanoplatform.
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Inflamación , Daño por Reperfusión Miocárdica , Nanopartículas , Animales , Ratones , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/patología , Inflamación/metabolismo , Nanopartículas/química , Flavonoides/farmacología , Flavonoides/química , Materiales Biomiméticos/farmacología , Materiales Biomiméticos/química , Humanos , Ratones Endogámicos C57BL , Masculino , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Neovascularización Fisiológica/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Movimiento Celular/efectos de los fármacos , Células RAW 264.7 , Tamaño de la Partícula , AngiogénesisRESUMEN
Purpose: Mitochondrial damage may lead to uncontrolled oxidative stress and massive apoptosis, and thus plays a pivotal role in the pathological processes of myocardial ischemia-reperfusion (I/R) injury. However, it is difficult for the drugs such as puerarin (PUE) to reach the mitochondrial lesion due to lack of targeting ability, which seriously affects the expected efficacy of drug therapy for myocardial I/R injury. Methods: We prepared triphenylphosphonium (TPP) cations and ischemic myocardium-targeting peptide (IMTP) co-modified puerarin-loaded liposomes (PUE@T/I-L), which effectively deliver the drug to mitochondria and improve the effectiveness of PUE in reducing myocardial I/R injury. Results: In vitro test results showed that PUE@T/I-L had sustained release and excellent hemocompatibility. Fluorescence test results showed that TPP cations and IMTP double-modified liposomes (T/I-L) enhanced the intracellular uptake, escaped lysosomal capture and promoted drug targeting into the mitochondria. Notably, PUE@T/I-L inhibited the opening of the mitochondrial permeability transition pore, reduced intracellular reactive oxygen species (ROS) levels and increased superoxide dismutase (SOD) levels, thereby decreasing the percentage of Hoechst-positive cells and improving the survival of hypoxia-reoxygenated (H/R)-injured H9c2 cells. In a mouse myocardial I/R injury model, PUE@T/I-L showed a significant myocardial protective effect against myocardial I/R injury by protecting mitochondrial integrity, reducing myocardial apoptosis and decreasing infarct size. Conclusion: This drug delivery system exhibited excellent mitochondrial targeting and reduction of myocardial apoptosis, which endowed it with good potential extension value in the precise treatment of myocardial I/R injury.
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Isoflavonas , Liposomas , Daño por Reperfusión Miocárdica , Compuestos Organofosforados , Animales , Liposomas/química , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Isoflavonas/química , Isoflavonas/farmacología , Isoflavonas/administración & dosificación , Isoflavonas/farmacocinética , Compuestos Organofosforados/química , Compuestos Organofosforados/farmacología , Compuestos Organofosforados/administración & dosificación , Compuestos Organofosforados/farmacocinética , Masculino , Ratones , Apoptosis/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Cationes/química , Miocardio/patología , Miocardio/metabolismo , Estrés Oxidativo/efectos de los fármacos , Péptidos/química , Péptidos/farmacología , Péptidos/administración & dosificación , Sistemas de Liberación de Medicamentos/métodosRESUMEN
Background: Myocardial ischemia-reperfusion injury (MIRI) refers to severe damage to the ischemic myocardium following the restoration of blood flow, and it is a major complication of reperfusion therapy for myocardial infarction. Notably, drugs such as metoprolol have been utilized to reduce ischemia-reperfusion injury. Tanshinone IIA is a major constituent extracted from Salvia miltiorrhiza Bunge. Recently, tanshinone IIA has been studied extensively in animal models for controlling MIRI. Therefore, we conducted a meta-analysis on the application of tanshinone IIA in rat models with MIRI to evaluate the therapeutic effects of tanshinone IIA. Methods: A comprehensive search was conducted across PubMed, Web of Science, Embase, the Cochrane Library, the China National Knowledge Infrastructure database, the Wanfang database, and the Chinese Scientific Journal Database to gather studies on tanshinone IIA intervention in rat models with MIRI.We employed SYRCLE's risk of bias tool to assess study quality. The primary outcome indicators were superoxide dismutase (SOD) and malondialdehyde (MDA). Myocardial infarction area was a secondary outcome indicator. This study was registered at PROSPERO (registration number CRD 42022344447). Results: According to the inclusion and exclusion criteria, 15 eligible studies were selected from 295 initially identified studies. In rat models with MIRI, tanshinone IIA significantly increased SOD levels while reducing MDA levels and myocardial infarction area. Moreover, the duration of myocardial ischemia influenced the effectiveness of tanshinone IIA. However, additional high-quality research studies are needed to establish the efficacy and definitive guidelines for the use of tanshinone IIA. Animal studies demonstrated that tanshinone IIA exerted a significant therapeutic effect when the ischemia duration was less than 40 minutes. Tanshinone IIA was found to be more effective when administered via intravenous, intraperitoneal, and intragastric routes at doses above 5 mg/kg. Additionally, treatment with tanshinone IIA at all stages-prior to myocardial ischemia, after ischemia but before reperfusion, prior to ischemia and after reperfusion, and after reperfusion-showed satisfactory results. Conclusions: Tanshinone IIA enhanced SOD activity and reduced MDA levels, thereby ameliorating oxidative stress damage during MIRI. Additionally, it reduced the myocardial infarction area, indicating its effectiveness in mitigating MIRI-induced damage in rats and demonstrating a myocardial protective effect. These findings contribute valuable insights for developing MIRI treatment strategies.
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Abietanos , Modelos Animales de Enfermedad , Daño por Reperfusión Miocárdica , Abietanos/farmacología , Abietanos/uso terapéutico , Animales , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Ratas , Superóxido Dismutasa/metabolismo , Malondialdehído/metabolismo , Infarto del Miocardio/tratamiento farmacológicoRESUMEN
Myocardial ischemia is a disease characterized by high morbidity and mortality rates, restoring blood supply to the ischemic area through reperfusion is an effective intervention method. However, numerous studies have shown that reperfusion may cause severe myocardial damage, resulting in myocardial systolic and diastolic dysfunction and seriously affecting myocardial function. This phenomenon is called myocardial ischemia reperfusion injury(MIRI). The physiological and pathological mechanisms of MIRI include oxidative stress, calcium overload, autophagy, pyrolysis, endoplasmic reticulum stress, apoptosis, etc. Oxidative stress plays an important role in MIRI-related cell death and is considered to be the main mechanism of MIRI. The occurrence of oxidative stress is mainly due to the excessive production of reactive oxygen species(ROS), which disrupts the balance of the redox system of the body or tissue. A large number of highly reactive ROS exceed the antioxidant defense capacity of cardiomyocytes, causing modifications in biological macromolecules such as DNA and proteins and resulting in severe reactions like DNA damage, protein dysfunction, cell damage or death, and local inflammation. Oxidative stress mediates apoptosis, autophagy, and inflammatory injury through various pathways, resulting in irreversible cardiomyocyte injury and myocardial dysfunction, which brings significant challenges for clinical treatment and prognosis. In recent years, remarkable progress has been made in understanding oxidative stress in ischemia reperfusion(I/R) injury of different organs and tissue. However, the injury mechanism caused by oxidative stress in restoring blood supply to the ischemic area and the protective effect of TCM remain largely unexplored. This article reviewed the role of oxidative stress in MIRI, the main production pathways of ROS, and the protective effects of TCM on oxidative stress injury during ischemic myocardial reperfusion, so as to provide a reference for future research and clinical treatment in this field.
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Medicamentos Herbarios Chinos , Daño por Reperfusión Miocárdica , Estrés Oxidativo , Estrés Oxidativo/efectos de los fármacos , Humanos , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/metabolismo , Medicamentos Herbarios Chinos/farmacología , Animales , Especies Reactivas de Oxígeno/metabolismo , Apoptosis/efectos de los fármacos , Sustancias Protectoras/farmacologíaRESUMEN
It has been suggested that sodium-glucose cotransporter 2 (SGLT2) inhibitors have cardioprotective effects during myocardial ischemia/reperfusion (I/R) independent of glucose-lowering action. However, the effects of SGLT2 inhibitors on structural damage to cardiomyocytes in the ischemic region during I/R remain unknown. We applied a microdialysis technique to the heart of anesthetized rats and investigated the effects of an SGLT2 inhibitor, dapagliflozin, on myocardial interstitial myoglobin levels in the ischemic region during coronary occlusion followed by reperfusion. Dapagliflozin was administered systemically (40 µg/body iv) or locally via a dialysis probe (100 µM and 1 mM) 30 min before coronary occlusion. In the vehicle group, coronary occlusion increased the dialysate myoglobin concentration in the ischemic region. Reperfusion further increased the dialysate myoglobin concentration. Intravenous administration of dapagliflozin reduced dialysate myoglobin concentration during ischemia and at 0-15 min after reperfusion, but local administration (100 µM and 1 mM) did not. Therefore, acute systemic administration of dapagliflozin prior to ischemia has cardioprotective effects on structural damage during I/R.
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Compuestos de Bencidrilo , Glucósidos , Daño por Reperfusión Miocárdica , Miocitos Cardíacos , Mioglobina , Animales , Compuestos de Bencidrilo/farmacología , Mioglobina/metabolismo , Glucósidos/farmacología , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Ratas , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Masculino , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , MicrodiálisisRESUMEN
Dexmedetomidine (Dex) is widely used in the sedation in intensive care units and as an anesthetic adjunct. Considering the anti-inflammatory and antioxidant properties of Dex, we applied in vivo rat model as well as in vitro cardiomyocyte models (embryonic rat cardiomyocytes H9c2 cells and neonatal rat cardiomyocytes, NRCMs) to evaluate the effects of Dex against myocardial ischemia reperfusion (I/R) injury. Transcriptomic sequencing for gene expression in heart tissues from control rats and Dex-treated rats identified that genes related to fatty acid metabolism were significantly regulated by Dex. Among these genes, the elongation of long-chain fatty acids (ELOVL) family member 6 (Elovl6) was most increased upon Dex-treatment. By comparing the effects of Dex on both wild type and Elovl6-knockdown H9c2 cells and NRCMs under oxygen-glucose deprivation/reoxygenation (OGD/R) challenge, we found that Elovl6 knockdown attenuated the protection efficiency of Dex, which was supported by the cytotoxicity endpoints (cell viability and lactate dehydrogenase release) and apoptosis as well as key gene expressions. These results indicate that Dex exhibited the protective function against myocardial I/R injury via fatty acid metabolism pathways and Elovl6 plays a key role in the process, which was further confirmed using palmitate exposure in both cells, as well as in an in vivo rat model. Overall, this study systematically evaluates the protective effects of Dex on the myocardial I/R injury and provides better understanding on the fatty acid metabolism underlying the beneficial effects of Dex.
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Apoptosis , Dexmedetomidina , Elongasas de Ácidos Grasos , Ácidos Grasos , Daño por Reperfusión Miocárdica , Miocitos Cardíacos , Animales , Dexmedetomidina/farmacología , Dexmedetomidina/uso terapéutico , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/metabolismo , Elongasas de Ácidos Grasos/genética , Elongasas de Ácidos Grasos/metabolismo , Ratas , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Ácidos Grasos/metabolismo , Masculino , Línea Celular , Apoptosis/efectos de los fármacos , Ratas Sprague-Dawley , Acetiltransferasas/metabolismo , Acetiltransferasas/genética , Supervivencia Celular/efectos de los fármacosRESUMEN
We herein report a study on the antioxidant peptides that show potential in alleviating myocardial ischemia reperfusion injury (MI/RI). Yak skin gelatin fraction Ac (YSG-Ac), obtained through ultrafiltration and gel filtration with Sephadex G-15, exhibits a favorable nutrient composition, high foaming capacity and stability, and resistance against gastrointestinal digestion. LC-MS/MS analysis reveals that YSG-Ac contains 26 peptide segments with sequence lengths of 8 to 12 amino acids. Online screening suggests that the antioxidant capacity of YSG-Ac is mainly attributed to the presence of hydrophobic and antioxidant amino acids. In vitro, our results demonstrate the MI/RI protective effects of YSG-Ac by effectively repairing H2O2-induced oxidative damage in H9c2 cells, which is achieved by inhibiting malondialdehyde (MDA) levels, and increasing glutathione peroxidase (GSH-pX) and superoxide dismutase (SOD) activity. In vivo, our results further confirm the effectiveness of YSG-Ac in narrowing the area of myocardial infarction, decreasing MDA levels, increasing SOD activity, and reducing the content of lactate dehydrogenase (LDH) in a mouse MI/RI model. Molecular docking analysis indicates that PGADGQPGAK with xanthine dehydrogenase (XDH) and GAAGPTGPIGS with tumor necrosis factor-alpha (TNF-α) exhibit strong bonding capability, and other related targets also show certain binding ability toward YSG-Ac. This suggests that YSG-Ac can regulate MI/RI through multiple targets and pathways. Overall, our findings highlight the potential of YSG-Ac as a functional food ingredient with antioxidant and MI/RI protective characteristics.