Second-generation antipsychotics induce cardiotoxicity by disrupting spliceosome signaling: Implications from...

Area of Science:

• Cardiovascular Pharmacology
• Molecular Toxicology
• Genomics and Proteomics

Background:

• Second-generation antipsychotics (SGAs) are widely used for mental disorders.
• Clinically significant cardiotoxicity associated with SGAs limits their therapeutic application.
• Identifying the shared molecular mechanisms of SGA-induced cardiotoxicity is crucial for patient safety.

Purpose of the Study:

• To elucidate the common molecular mechanism underlying cardiotoxicity induced by second-generation antipsychotics (SGAs).
• To investigate the role of spliceosome signaling in SGA-induced cardiac damage.
• To explore potential therapeutic strategies targeting spliceosome dysfunction.

Main Methods:

• Dual-omics analysis (proteomics and RNA sequencing) in Balb/C mice treated with olanzapine and clozapine.
• In vivo validation of differentially expressed spliceosome proteins.
• Assessment of alternative splicing events and pathway dysregulation.
• Pharmacological intervention using a spliceosome inhibitor (Pladienolide B).

Main Results:

• SGAs induced progressive cardiomyocyte degeneration, inflammation, and fibrosis in mouse hearts.
• Proteomic analysis identified 22 overlapping differentially expressed proteins, enriched in spliceosome-related functions.
• SGA treatment significantly enhanced alternative splicing events, leading to transcriptomic dysregulation.
• Inhibition of mRNA splicing with Pladienolide B attenuated SGA-induced cardiac damage and inflammation.

Conclusions:

• Spliceosome signaling dysregulation is a common mechanistic pathway driving second-generation antipsychotic cardiotoxicity.
• Targeting spliceosome signaling represents a promising therapeutic strategy to mitigate SGA-induced cardiac adverse effects.
• This study provides novel insights into the molecular basis of drug-induced cardiotoxicity.