PTEN Regulates Myofibroblast Activation in Valvular Interstitial Cells based on Subcellular Localization.

Area of Science:

• Cardiovascular Biology
• Cellular Biology
• Fibrosis Research

Background:

• Aortic valve stenosis (AVS) involves disrupted aortic valve mechanics and left ventricle hypotrophy.
• Activation of valvular interstitial cells (VICs) into myofibroblasts, marked by αSMA, is a key feature of AVS.
• The tumor suppressor PTEN's role in tissue fibrosis suggests its potential involvement in AVS.

Purpose of the Study:

• To investigate the role of PTEN in regulating myofibroblast activation in VICs.
• To determine if PTEN acts as a protective factor against matrix-induced VIC activation in AVS.
• To explore PTEN's potential as a therapeutic target for AVS.

Main Methods:

• Analysis of PTEN levels in human aortic valve samples (healthy vs. diseased).
• Pharmacological and genetic manipulation of PTEN in VIC cultures.
• Assessment of myofibroblast activation markers and nuclear PTEN localization under varying matrix stiffness.

Main Results:

• Human diseased aortic valves showed lower PTEN levels compared to healthy valves.
• PTEN overexpression inhibited stiffness-induced VIC myofibroblast activation.
• PTEN inhibition exacerbated myofibroblast activation.
• Increased nuclear PTEN localization correlated with smaller nuclei, altered histone expression, and a quiescent fibroblast phenotype.

Conclusions:

• PTEN suppresses VIC activation and promotes fibroblast quiescence in the context of AVS.
• Reduced PTEN levels are associated with AVS pathology.
• PTEN represents a potential pharmacological target for treating aortic valve stenosis.