Phospholipase Cε insufficiency causes ascending aortic aneurysm and dissection

Area of Science:

• Cardiovascular Biology
• Molecular Genetics
• Vascular Medicine

Background:

• Phospholipase Cε (PLCε) is involved in various physiological processes.
• Its specific role in thoracic aortic aneurysm and dissection (TAAD) is not well understood.
• PLCε deficiency is linked to aortic valve disorders.

Purpose of the Study:

• To investigate the role of PLCε in the development of TAAD.
• To determine if PLCε deficiency exacerbates angiotensin II-induced aortic disease.
• To explore the association of PLCε genetic variants with human aortic dissection.

Main Methods:

• Utilized PLCε-deficient mice and wild-type littermates.
• Administered angiotensin II (ANG II) infusion to induce aortic dilation and dissection.
• Performed histological analysis for medial degeneration and TAAD.
• Analyzed gene expression via RNA sequencing.
• Screened whole exome sequences of patients with type A dissection for PLCE1 variants.

Main Results:

• PLCε-deficient mice exhibited aortic valve insufficiency and ascending aortic dilation.
• ANG II infusion caused significantly higher rates of sudden death from aortic dissection in PLCε-deficient mice compared to controls.
• PLCε deficiency led to increased medial degeneration and TAAD following ANG II treatment.
• RNA sequencing revealed upregulation of inflammatory and fibrotic pathways.
• Identified rare nonsynonymous PLCE1 variants in patients with type A aortic dissection.

Conclusions:

• PLCε deficiency predisposes to aortic valve insufficiency and TAAD, particularly under hypertensive stress.
• PLCε plays a critical role in maintaining aortic integrity.
• PLCE1 variants may contribute to the pathogenesis of human aortic dissection and insufficiency.