Clin Res Cardiol (2021)
DOI DOI https://doi.org/10.1007/s00392-021-01843-w
Tubulin-folding cofactor E deficiency impairs flow mediated arterial dilatation and promotes vascular dysfunction
M. Molitor1, P. Efentakis1, K. Kossmann1, M. Bochenek2, J. Wild3, L. Lagrange2, S. Finger4, R. Jung2, S. Karbach1, K. Schäfer3, A. Schulz5, P. S. Wild5, T. Münzel3, P. Wenzel1
1Zentrum für Kardiologie, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz; 2Centrum für Thrombose und Hämostase, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz; 3Kardiologie 1, Zentrum für Kardiologie, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz; 4Abteilung für psychosomatische Medizin, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz; 5Präventive Kardiologie und Medizinische Prävention, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz;

Objectives:
Assessment of endothelial function in humans by measuring flow mediated dilatation (FMD) risk-stratifies patients with established cardiovascular diseases, whereas its predictive value is limited in the setting of primary prevention. In this study we aimed to discover and evaluate novel markers of FMD on a population-based level by a Genome Wide Association Study (GWAS). We transferred our results from bedside to benchand created specific knockout mice in order to investigate the role of the novel genes on vascular smooth muscle cells for vascular function


Methods and Results:

GWAS of 5,000 participants in the Gutenberg Health Study (GHS) was performed in order to identify novel genome single nucleotide polymorphisms (SNPs) correlated with endothelial dysfunction and FMD. GHS revealed that SNPs rs6675944 (T→C) and rs1205889 (T→G) in chromosome 1 are negatively correlated with flow mediated dilation (FMD) of the brachial artery (rs6675944 β=-0.4841, P=5.9e-27, R2tot=0.006 and β=-0.4841, P=2.3e-12, R2tot=0.006 ; rs12405889 β=-0.5028, P=8.8e-14, R2tot=0.006 and β=-0.5028, P=1.0e-25, R2tot=0.006). Both

SNPs were found in the tubulin folding cofactor E (or Tubulin-specific chaperone E, TBCE) gene region. mRNA expression analysis of peripheral blood mononuclear cells (PBMCs) obtained from GHS-enrolled individuals revealed that the SNPs were negatively associated with TBCE expression (β estimate: -0.4841, R2tot=0.010). 

To further investigate the novel GWAS results, SMMHC-ERT2Cre+/-TBCEfl/flmice were generated with a conditional knockdown of TBCE in smooth muscle cells. Mice were fed with tamoxifen food for 6 weeks starting at the age of 5-6 weeks (Estrogen receptor 2-ERT2 promotor)
and challenged with angiotensin II (AngII). SMMHC-ERT2Cre+/-TBCEfl/flaortas showed reduced response to PDGF2αcontraction compared to controls. SMMHC-ERT2Cre+/-TBCEfl/flmice were characterized by increased aortic stiffness, further exacerbated by AngII in vivo. SMMHC-
ERT2Cre+/-TBCEfl/flaortas presented endothelial dysfunction at baseline compared to their controls, demonstrated by impaired relaxation in response to Ach. Vascular dysfunction was accompanied by an increased left common carotid artery (LCCA) Resistance and Pulsatility
indexes 


Conclusion:
Taken together, SNPs rs6675944 and rs12405889 are negatively correlated with Tubulin-folding cofactor E (TBCE)expression and FMD on a population-based level.VSMC targeted TBCE ablation leads to a vascular dysfunction and stiffness, which is exacerbated by AngII.
https://dgk.org/kongress_programme/jt2021/aV1326.html