Statins improve endothelial function via suppression of epigenetic-driven EndMT.

Area of Science:

• Cardiovascular Biology
• Epigenetics
• Stem Cell Biology

Background:

• Statins offer cardiovascular benefits beyond lipid-lowering, but mechanisms are unclear.
• Endothelial-to-mesenchymal transition (EndMT) contributes to cardiovascular diseases.
• Diabetic conditions exacerbate endothelial dysfunction.

Purpose of the Study:

• Investigate simvastatin's non-lipid-lowering effects on endothelial cells.
• Elucidate the role of the YAP signaling pathway in simvastatin's protective effects.
• Identify molecular targets mediating simvastatin's impact on EndMT.

Main Methods:

• Utilized human induced pluripotent stem cell-derived endothelial cells (hiPSC-ECs).
• Assessed simvastatin's effects on chromatin accessibility and gene expression.
• Examined the geranylgeranyltransferase (GGTase) I-RhoA-YAP signaling axis.
• Investigated SOX9 enhancer activity and EndMT markers in vitro and in vivo.

Main Results:

• Simvastatin improved hiPSC-EC function under baseline and diabetic conditions.
• Simvastatin reduced chromatin accessibility at EndMT-regulating genes in a YAP-dependent manner.
• Inhibition of GGTase I disrupted YAP nuclear translocation and activity via RhoA antagonism.
• A novel SOX9 enhancer promoting EndMT was identified downstream of statin-YAP signaling.
• Targeting the GGTase-RhoA-YAP-SOX9 axis rescued endothelial dysfunction.

Conclusions:

• Simvastatin exerts protective effects against endothelial dysfunction by epigenetically repressing EndMT.
• The GGTase-RhoA-YAP-SOX9 pathway is a key mediator of simvastatin's action.
• This study reveals a novel epigenetic mechanism for statin-based cardiovascular protection, especially relevant in diabetes.