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Protective Effects of Pt-N-C Nanozymes against Myocardial Ischemia-reperfusion Injury

ABSTRACT: Effective therapeutic strategies for myocardial ischemia/reperfusion (I/R) injury are still lacking. Targeting reactive oxygen species (ROS), the major cause of I/R injury, provides a practical approach to alleviate myocardial damage after reperfusion procedure. Herein, we synthesized an innovative antioxidant nanozyme equipped with single-platinum-atom (PtsaN-C) for protecting against I/R injury. PtsaN-C exhibited potent multiple enzyme-mimicking activities with high-efficiency ROS-scavenging. Mechanistic studies demonstrated that excellent ROS-elimination performance in single platinum atom center was prior to that of platinum cluster center attributing to good synergistic effect and metallic electronic property with nitrogen-doping coordination structure. Systematic in vitro and in vivo studies confirmed that PtsaN-C counteracted ROS efficiently to restore cellular homeostasis and prevented apoptotic progress after I/R injury. PtsaN-C presented excellent biocompatibility and biosafety, making it promising for future clinical application. Current study broadens the horizon of single-atom nanomedicine against ROS-induced damage, offering a promising therapeutic avenue for treatment of I/R injury.

ORGANISM(S): Mus Musculus

SUBMITTER: Chengxing Shen

PROVIDER: PXD048584 | iProX | Tue Jan 16 00:00:00 GMT 2024

REPOSITORIES: iProX

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Protective effects of Pt-N-C single-atom nanozymes against myocardial ischemia-reperfusion injury.

Ye Tianbao T Chen Cheng C Wang Di D Huang Chengjie C Yan Zhiwen Z Chen Yu Y Jin Xian X Wang Xiuyuan X Ding Xianting X Shen Chengxing C

Nature communications 20240223 1

Effective therapeutic strategies for myocardial ischemia/reperfusion (I/R) injury remain elusive. Targeting reactive oxygen species (ROS) provides a practical approach to mitigate myocardial damage following reperfusion. In this study, we synthesize an antioxidant nanozyme, equipped with a single-Platinum (Pt)-atom (PtsaN-C), for protecting against I/R injury. PtsaN-C exhibits multiple enzyme-mimicking activities for ROS scavenging with high efficiency and stability. Mechanistic studies demonstr ...[more]

PMID: 38396113

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Project description:The management of cardiac ischemic injury has been challenged by ischemia and reperfusion (I/R) injury. Reactive oxygen species (ROS) generated from mitochondrial reverse electron transport (RET) during the early phase of reperfusion is considered to be the initiating cause for ischemia and reperfusion injury. Ginsenosides and their prescriptions are widely used in the clinic for treatment of myocardial ischemia, however, the action to combat ROS remains to be elucidated. In this work, we used TMT-based proteomic approach to detect differential proteins from mitochondrial fractions of mice hearts with ischemia-reperfusion. Results indicated that the mass error of identified peptides was within 10 ppm, and most of the identified peptides were composed of 7-23 amino acids. Using these qualified data, 17,262 peptides, with a confidence level ≥ 95%, were mapped to 3,054 protein groups. PCA analysis showed that the model group was clearly separated from the blank group, while the protein pattern was partly reversed with Rb1 treatment. With a criteria of p-value < 0.05, 591 significantly changed proteins including 186 increased and 405 decreased ones in the model group were identified compared with the blank group. These proteins were divided into 4 clusters. Proteins in Cluster I highly increased in the model group, but clearly decreased in the Rb1 group. Proteins in Cluster IV clearly decreased in the model group, but markedly increased in the Rb1 group. Proteins in Cluster III and in Cluster IV were not significantly or slightly regulated by the Rb1 treatment. GO analysis of Cluster I and II indicated that the molecular function of these proteins were closely related to oxidoreductase activity and NADH dehydrogenase activity. Our result showed that Rb1 administration before ischemia markedly decreased infarct size (48 h post-I/R), and preserved cardiac function (2 weeks post-I/R), and subsequently limited tissue fibrosis (28 days post-I/R). These results indicated that targeted inhibition of mitochondrial complex I in the early stage of reperfusion by Rb1 is a potential therapeutic strategy for alleviating IR injury. This work not only indicates a potent molecular target for the precision therapy of myocardial ischemia by Rb1, but also provides novel knowledge for the management of cardiac ischemic injury by traditional Chinese medicine.

Project description:Myocardial ischemic preconditioning (IPC) enhances myocardial resilience to ischemic injury. Myocardial stunning is a transient, reversible dysfunction, while necrosis involves irreversible cell death. The relationship between IPC, stunning, and necrosis is not well understood, requiring further molecular investigation. This study aimed to investigate the proteomic changes associated with IPC, focusing on its relationship with myocardial stunning and necrosis. A novel 13.5-minute ischemia-reperfusion (I/R) rat model was specifically chosen to induce myocardial stunning, providing a unique approach to assess IPC effects in this context. Rats underwent either IPC with two 5-minute ischemia/reperfusion cycles followed by a 13.5-minute ischemic period or the procedure without IPC (no ischemic preconditioning, NIPC). Myocardial samples were collected at early (T1) and 4-hour post-reperfusion (T2) time points for proteomic analysis. Protein levels were quantified by differential labeling using TMTpro reagents, and subsequent liquid chromatography-mass spectrometry. IPC induced upregulation of proteins involved in endocytosis and Fc gamma R-mediated phagocytosis pathways at T1, while downregulating proteins related to tissue remodeling, immune response, and coagulation at T2. Conversely, NIPC exhibited upregulation of proteins associated with tissue damage and inflammation. IPC rats demonstrated enhanced leukocyte migration, complement activation, and immune response between T1 and T2. Consistent proteomic changes were observed between T1 and T2 in IPC vs. NIPC groups, and common alterations between IPC T2 vs. T1 and NIPC T2 vs. T1 comparisons underline shared pathways in cardiac complement and coagulation cascades. Our study reveals distinct proteomic changes induced by IPC in the context of myocardial stunning and necrosis. IPC activates early protective pathways, attenuates tissue damage and inflammation, and preserves myocardial function. These findings underscore IPC's reparative potential and identify myocardial stunning as an important, transient adaptation, which may have implications for supportive clinical management in I/R.

Dataset Information

Protective Effects of Pt-N-C Nanozymes against Myocardial Ischemia-reperfusion Injury

Publications

Protective effects of Pt-N-C single-atom nanozymes against myocardial ischemia-reperfusion injury.

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