Tubulin-folding cofactor E deficiency promotes vascular dysfunction by increased endoplasmic reticulum stress

Area of Science:

• Cardiovascular Research
• Genetics
• Molecular Biology

Background:

• Flow-mediated dilation (FMD) assesses endothelial function but has limited predictive value in primary prevention.
• Novel markers for FMD are needed for population-level risk stratification.
• Established cardiovascular disease patients benefit from FMD risk stratification.

Purpose of the Study:

• To identify novel markers negatively correlated with FMD.
• To investigate the contribution of novel targets to vascular function.
• To evaluate TBCE as a potential therapeutic target for vascular dysfunction.

Main Methods:

• Genome-wide association study (GWAS) of 4175 participants.
• Generation and characterization of conditional knockout mouse models.
• Analysis of single-nucleotide polymorphisms (SNPs) and gene expression.

Main Results:

• GWAS identified SNPs in the TBCE gene negatively correlated with FMD and TBCE expression.
• TBCE deficiency in mice led to endothelial dysfunction, aortic hypertrophy, and ER stress-mediated VSMC hyperproliferation.
• ER stress exacerbated vascular dysfunction, while tauroursodeoxycholic acid treatment reversed it.

Conclusions:

• TBCE and tubulin homeostasis are novel predictors of vascular function.
• TBCE represents a potential drug target for ER stress-dependent vascular dysfunction.
• Targeting ER stress pathways may ameliorate vascular dysfunction.