Background Dilated cardiomyopathy remains a leading cause of heart failure worldwide. Immune inflammation response is recognized as a significant player in the progression of heart failure; however, immunomodulatory strategies remain a long‐term challenge. Colchicine, a potent anti‐inflammatory drug, has many benefits in ischemic cardiovascular events, but its role in nonischemic heart failure remains unclear. Methods and Results Doxorubicin administration was used to establish a murine dilated cardiomyopathy model, and colchicine or saline was orally given. At the end point, cardiac function and fibrosis were measured to investigate the effects of colchicine. Inflammatory cytokine levels, neutrophil recruitment, and NLRP3 (NOD‐like receptor protein 3) inflammasome activation were detected to evaluate the inflammatory response. Furthermore, to examine the downstream target of colchicine, SIRT2 (Sirtuin 2) was pharmacologically inhibited in vitro; thus, changes in the NLRP3 inflammasome were detected by immunoblotting. These results showed that murine cardiac function was significantly improved and fibrosis was significantly alleviated after colchicine treatment. Moreover, the infiltration of neutrophils and the levels of inflammatory cytokines in the failing myocardium were both decreased by colchicine treatment. Mechanistically, colchicine upregulated the expression of SIRT2, leading to the inactivation of the NLRP3 inflammasome in an NLRP3 deacetylated manner. Conversely, the inhibition of SIRT2 attenuated the suppressive effect of colchicine on NLRP3 inflammasome activation. Conclusions This study indicated that colchicine could be a promising therapeutic candidate for dilated cardiomyopathy and other nonischemic heart failure associated with the inflammatory response.
Doxorubicin (Dox) is an anticancer drug widely used in tumor chemotherapy, but it has the side-effect of cardiotoxicity, which is closely related to mitochondrial damage. Mitochondrial dynamics is a quality control mechanism that usually helps to maintain a healthy mitochondrial pool. Trophoblast stem cell-derived exosomes (TSC-Exos) have been shown to protect cardiomyocytes from DOX-induced cardiotoxicity. To explore whether the cardioprotective role is mediated by the regulation of mitochondrial dynamic mechanism, TSC-Exos were isolated from human trophoblast stem cells by ultracentrifugation and characterized by Western blot and transmission electron microscopy. Cellular experiments of H9c2 cardiomyocytes co-cultured with Dox and TSC-Exos were performed in vitro to determine the levels of reactive oxygen species generation and apoptosis level. An animal model of heart failure was established by intraperitoneal injection of Dox in vivo, therapy mice were received additional intracardiac injection of TSC-Exos, then, the cardiac function, cardiomyocyte apoptosis and mitochondrial fragmentation were ameliorated. Histology assays suggest that Dox caused an increased tendency of mitochondrial fission, which was manifested by a decrease in the average size of mitochondria. By receiving TSC-Exos treatment, this effect was eliminated. In summary, these results suggest that TSC-Exos alleviate DOX-induced cardiotoxicity through antiapoptotic effect and improving mitochondrial fusion with an increase in Mfn2 expression. This study is the first to provide a potential new treatment scheme for the treatment of heart failure from the perspective of the relationship between TSC-Exos and mitochondrial dynamics.
BackgroundInhibition of sympathetic activity and renin–angiotensin system with renal denervation (RDN) was proved to be effective in managing refractory hypertension, and improving left ventricular (LV) performance in chronic heart failure. The inhibition of sustained sympathetic activation prevents or delays the development of cardiac fibrosis and dysfunction that occurs after myocardial infarction and ischemia–reperfusion (I/R) injury. The translational efficiency of RDN remains to be defined in preclinical animal studies.ObjectivesThis study investigated the therapeutic role of RDN in adverse remodeling and intramyocardial inflammation in myocardial ischemia–reperfusion (MI/R) injury.MethodsHerein, 15 minipigs were subjected to 90-min percutaneous occlusion of the left anterior descending artery followed by reperfusion. Eight animals received simultaneous RDN using catheter-based radiofrequency ablation (MI/R-RDN). Cardiac function and infarct volume were measured in vivo, followed by histological and biochemical analyses.ResultsThe infarct volume in I/R-RDN pigs reduced at 30 days postreperfusion, compared to I/R-Sham animals. The levels of catecholamine and cytokines in the serum, kidney cortex, the border, and infarcted regions of the heart were significantly reduced in I/R-RDN group. Moreover, the gene expression of collagen and the protein expression of adrenergic receptor beta 1 in heart were also decreased in I/R-RDN mice. Additionally, RDN therapy alleviated myocardial oxidative stress.ConclusionRDN is an effective therapeutic strategy for counteracting postreperfusion myocardial injury and dysfunction, and the application of RDN holds promising prospects in clinical practice.
Background Doxorubicin (DOX) has limited chemotherapy application for malignancies due to cardiotoxicity. The pathogenesis of DOX-induced cardiomyopathy (DiCM) is yet to be elucidated. Increasing studies proved that activation of AKT prevented cardiomyocyte apoptosis and cardiac dysfunction in response to DOX insult. Our previous studies indicated that major vault protein (MVP) deficiency was accompanied by suppressed phosphorylation of AKT in metabolic diseases. This study aimed to investigate the role and underlying mechanism of MVP on cardiomyocyte apoptosis in DiCM. Methods Mice were intraperitoneally injected with DOX 5 mg/kg, once a week for 5 weeks, the total cumulative dose was 25 mg/kg. Cardiomyocyte-specific MVP overexpression was achieved using an adeno-associated virus system under the cTnT promoter after the fourth DOX injection. Cardiac function was examined by echocardiography followed by euthanasia. Tissue and serum were collected for morphology analysis and biochemical examination. Results Herein, we found that MVP expression was upregulated in DOX-treated murine hearts. Cardiac-specific MVP overexpression alleviated DOX-induced cardiac dysfunction, oxidative stress and fibrosis. Mechanistically, MVP overexpression activated AKT signaling and decreased cardiomyocyte apoptosis in DiCM. Conclusions Based on these findings, we supposed that MVP was a potential therapeutic agent against DiCM.
Doxorubicin (Dox) is an anticancer drug widely used with the side-effect of cardiotoxicity. The cardiotoxicity of Dox is closely related to mitochondrial damage. Mitochondrial dynamics is a quality control mechanism that usually helps to maintain a healthy mitochondrial pool. Trophoblast stem cell-derived exosomes (TSC-Exos) have been shown to protect cardiomyocytes from DOX-induced cardiotoxicity. To explore whether the cardioprotective role is mediated by the regulation of mitochondrial dynamic mechanism, we isolated TSC-Exos from human trophoblast stem cells by ultracentrifugation and characterized them by Western blot and transmission electron microscopy. We performed cellular experiments with H9c2 cells co-cultured with Dox and TSC-Exos in vitro, and in vivo we established a heart failure model by intraperitoneal injection of Dox. Mice in the treatment group were received additional intracardiac injection of TSC-Exos. Then, the cardiac function, cardiomyocyte apoptosis and mitochondrial fragmentation of the treatment group were ameliorated.Dox caused an increased tendency of mitochondrial fission, which was manifested by a decrease in the average size of mitochondria. By receiving TSC-Exos treatment, this effect was eliminated, and its downstream molecular mechanism was investigated. In summary, these results suggested that TSC-Exos lesson DOX-induced cardiotoxicity through antiapoptotic effect and improving mitochondrial fusion with an increase in Mfn2 expression. Together, this study provides a potential new treatment scheme of TSC-Exos for the treatment of heart failure.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.