Fu Liu , Li-fang Lv , Fang-fang Bi , Qing-ming Pan , Ze-hong Jing , Chen Cui , Miao Cao , Tong Yu , Jin Li , Yi-jie He , Hong-wen Xiao , Hua Tian , Yun Wu , Hong-li Shan , Yu-hong Zhou
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ITFG2 as a NEDD4-2 inhibitor: Preserving calcium homeostasis to prevent myocardial ischemic injury
This study aimed to investigate the role of ITFG2, a protein highly expressed in cardiac tissues, in myocardial ischemic injury and its potential interactions with NEDD4-2. An in vivo myocardial infarction (MI) model was induced in mice via left anterior descending artery ligation, and ITFG2 expression was modulated using adeno-associated virus AAV9 vectors. Echocardiography was used to assess cardiac function, and primary mouse cardiomyocytes were cultured and subjected to hypoxia. ITFG2 expression was found to be significantly reduced following MI and in hypoxia-treated neonatal cardiomyocytes. Overexpression of ITFG2 improved cardiac contractility, reduced apoptosis, and stabilized calcium levels by inhibiting NEDD4-2-mediated ubiquitination of SERCA2a. Conversely, ITFG2 knockdown exacerbated calcium overload and cardiac dysfunction. Mechanistically, ITFG2 binds to NEDD4-2, decreasing its interaction with SERCA2a and preventing SERCA2a degradation. These findings suggest that ITFG2 acts as a critical inhibitor of NEDD4-2, preserving SERCA2a function and maintaining calcium homeostasis in cardiomyocytes under ischemic conditions. Therefore, ITFG2 may represent a potential therapeutic target for preventing myocardial ischemic injury and improving outcomes in MI patients.
期刊介绍:
Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics.
The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process.
All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review.
While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.