Topoisomerase 2B Decrease Results in Diastolic Dysfunction via p53 and Akt: A Novel Pathway | JoVE Visualize

Area of Science:

Cardiovascular Biology
Molecular Cardiology
Genetics

Background:

Diastolic dysfunction, characterized by ventricular stiffness, significantly contributes to cardiovascular mortality and morbidity.
Current pharmacological treatments for diastolic dysfunction have yielded negative clinical trial results.
A lack of accurate preclinical models hinders the development of effective therapies for diastolic dysfunction.

Purpose of the Study:

To develop a novel, genetically engineered mouse model that recapitulates key features of human diastolic dysfunction.
To investigate the role of Topoisomerase 2 beta (Top2b) in the pathogenesis of diastolic dysfunction.
To identify potential molecular mediators and therapeutic targets for diastolic dysfunction.

Main Methods:

Created a conditional, tissue-specific, inducible Topoisomerase 2 beta (Top2b) knockout mouse model in the heart.
Utilized echocardiography and pressure-volume loop analysis to assess left ventricular function.
Performed histological analysis, cellular morphology studies, and reverse phase protein analysis on myocardial samples.
Confirmed molecular findings in myocardial biopsy samples from human patients with diastolic dysfunction.

Main Results:

The Top2b knockout mice exhibited echocardiographic and invasive hemodynamic features consistent with diastolic dysfunction.
Histological examination and cellular analysis revealed morphological and molecular changes mirroring human diastolic dysfunction.
Reverse phase protein analysis indicated activation of p53 and inhibition of Akt signaling pathways.
Elevated p53 and reduced Akt activity were confirmed in human diastolic dysfunction myocardial biopsies.

Conclusions:

A novel Top2b-downregulated preclinical mouse model for diastolic dysfunction has been established.
The study identifies p53 activation and Akt inhibition as potential key mediators in diastolic dysfunction.
These findings suggest Top2b, p53, and Akt as promising targets for future therapeutic interventions in diastolic dysfunction.