Cardiac PTN-SlRT1 axis alleviates oxidative stress and promotes mitochondrial energy reprogramming to mitigate doxorubicin-induced cardiotoxicity through AMPK/PGC1α signalingOA
Doxorubicin(DOX)remains a cornerstone chemotherapeutic agent for malignancies,yet its clinical utility is severely limited by dose-dependent cardiotoxicity,which can lead to progressive left ventricular dysfunction and heart failure.Pleiotrophin(PTN),a heparin-binding growth factor with diverse physiological functions,regulates glucose and lipid metabolism and promotes oxidative energy pathways.However,whether PTN exerts protective effects against DOX-induced cardiotoxicity(DiC)remains unclear.In this study,we establish cellular and animal models of DlC.DOX administration induces pronounced myocardial injury in both models,characterized by impaired ventricular contractility,increased fibrotic remodeling,and reduced cell viability.Concurrently,PTN protein expression is significantly downregulated in cardiomyocytes under DOX treatment.Overexpression of PTN substantially alleviates these pathological changes.In vitro,PTN reduces mitochondrial oxidative stress and apoptosis while restoring energy production and cell viability.In vivo,PTN improves mitochondrial ultrastructure,decreases cardiomyocyte apoptosis,and enhances cardiac function.Mechanistically,PTN directly binds to SIRT1 and activates AMPK phosphorylation at Thr172,triggering a downstream cascade through the AMPK-PGC1α axis that reprograms mitochondrial energy metabolism and attenuates cardiotoxicity.In conclusion,the PTN-SIRT1 axis protects against DiC by reducing oxidative stress and promoting mitochondrial energy homeostasis via the AMPK/PGC1α pathway,highlighting its potential as a novel therapeutic target for preventing chemotherapy-related cardiac injury.
Yuxiao Sun;Tianwen Wei;Hongping Xu;Hongda Li;Chang Zhou;Xianliang Liu;Yafei Li;Shangwei Huang;Qi Zhang;Xia Duan
Department of Cardiology,Shanghai East Hospital,School of Medicine,Tongji University,Shanghai 200120,ChinaDepartment of Cardiology,Shanghai East Hospital,School of Medicine,Tongji University,Shanghai 200120,ChinaDepartment of Cardiology,Shanghai East Hospital,School of Medicine,Tongji University,Shanghai 200120,ChinaDepartment of Cardiology,Shanghai East Hospital,School of Medicine,Tongji University,Shanghai 200120,ChinaSchool of Medicine,Tongji University,Shanghai 200092,ChinaSchool of Nursing and Health Sciences,Hong Kong Metropolitan University,Hong Kong SAR,ChinaDepartment of Cardiology,the Affiliated Suzhou Hospital of Nanjing Medical University,Suzhou Municipal Hospital,Gusu School,Nanjing Medical University,Suzhou 215000,ChinaDepartment of Cardiology,Shanghai East Hospital,School of Medicine,Tongji University,Shanghai 200120,ChinaDepartment of Cardiology,Shanghai East Hospital,School of Medicine,Tongji University,Shanghai 200120,ChinaNursing Department,Shanghai Key Laboratory of Maternal Fetal Medicine,Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology,Shanghai First Maternity and Infant Hospital,School of Medicine,Tongji University,Shanghai 200092,China
医药卫生
doxorubicin-induced cardiotoxicitypleiotrophinoxidative stressmitochondrial energy metabolism
《Acta Biochimica et Biophysica Sinica》 2026 (2)
P.421-436,16
supprorted by the grants from the National Natural Science Foundation of China(No.82170477)the Key Disciplines Group Construction Project of Shanghai Pudong New Area Health Commission(No.PWZxq2022-02)the Clinical Research Project of the Three-Year Action Plan for the Disciplinary Construction of the"School of Nursing(in Preparation)"of Tongji University School of Medicine(No.JS2210313)the Important Weak Subject Construction Project of Shanghai Pudong New Area Health Commission(No.PWZbr2022-04)Shanghai East Hospital Youth Scientific Research Cultivation Fund(No.DFPY2024020)the Angel Plan and Young Nurse Growth Project of Shanghai East Hospital(No.DFTS-2227)the Fifth Batch of Technical Standardization Management and Promotion Projects of Shanghai Hospital Development Center(No.SHDC22024211)the General Program of Shanghai Municipal Health Commission(No.202340048).
评论