A proteomic atlas of the neointima identifies novel druggable targets for preventive therapy

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

A proteomic atlas of the neointima identifies novel druggable targets for preventive therapy. / Wierer, Michael; Werner, Julia; Wobst, Jana; Kastrati, Adnan; Cepele, Ganildo; Aherrahrou, Redouane; Sager, Hendrik B; Erdmann, Jeanette; Dichgans, Martin; Flockerzi, Veit; Civelek, Mete; Dietrich, Alexander; Mann, Matthias; Schunkert, Heribert; Kessler, Thorsten.

In: European Heart Journal, 08.04.2021.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Wierer, M, Werner, J, Wobst, J, Kastrati, A, Cepele, G, Aherrahrou, R, Sager, HB, Erdmann, J, Dichgans, M, Flockerzi, V, Civelek, M, Dietrich, A, Mann, M, Schunkert, H & Kessler, T 2021, 'A proteomic atlas of the neointima identifies novel druggable targets for preventive therapy', European Heart Journal. https://doi.org/10.1093/eurheartj/ehab140

APA

Wierer, M., Werner, J., Wobst, J., Kastrati, A., Cepele, G., Aherrahrou, R., Sager, H. B., Erdmann, J., Dichgans, M., Flockerzi, V., Civelek, M., Dietrich, A., Mann, M., Schunkert, H., & Kessler, T. (2021). A proteomic atlas of the neointima identifies novel druggable targets for preventive therapy. European Heart Journal. https://doi.org/10.1093/eurheartj/ehab140

Vancouver

Wierer M, Werner J, Wobst J, Kastrati A, Cepele G, Aherrahrou R et al. A proteomic atlas of the neointima identifies novel druggable targets for preventive therapy. European Heart Journal. 2021 Apr 8. https://doi.org/10.1093/eurheartj/ehab140

Author

Wierer, Michael ; Werner, Julia ; Wobst, Jana ; Kastrati, Adnan ; Cepele, Ganildo ; Aherrahrou, Redouane ; Sager, Hendrik B ; Erdmann, Jeanette ; Dichgans, Martin ; Flockerzi, Veit ; Civelek, Mete ; Dietrich, Alexander ; Mann, Matthias ; Schunkert, Heribert ; Kessler, Thorsten. / A proteomic atlas of the neointima identifies novel druggable targets for preventive therapy. In: European Heart Journal. 2021.

Bibtex

@article{06270a24ef434abb96fda03db48bb69f,
title = "A proteomic atlas of the neointima identifies novel druggable targets for preventive therapy",
abstract = "AIMS : In-stent restenosis is a complication after coronary stenting associated with morbidity and mortality. Here, we sought to investigate the molecular processes underlying neointima formation and to identify new treatment and prevention targets.METHODS AND RESULTS : Neointima formation was induced by wire injury in mouse femoral arteries. High-accuracy proteomic measurement of single femoral arteries to a depth of about 5000 proteins revealed massive proteome remodelling, with more than half of all proteins exhibiting expression differences between injured and non-injured vessels. We observed major changes in the composition of the extracellular matrix and cell migration processes. Among the latter, we identified the classical transient receptor potential channel 6 (TRPC6) to drive neointima formation. While Trpc6-/- mice presented reduced neointima formation compared to wild-type mice (1.44 ± 0.39 vs. 2.16 ± 0.48, P = 0.01), activating or repressing TRPC6 in human vascular smooth muscle cells resulted in increased [vehicle 156.9 ± 15.8 vs. 1-oleoyl-2-acetyl-sn-glycerol 179.1 ± 8.07 (103 pixels), P = 0.01] or decreased migratory capacity [vehicle 130.0 ± 26.1 vs. SAR7334 111.4 ± 38.0 (103 pixels), P = 0.04], respectively. In a cohort of individuals with angiographic follow-up (n = 3068, males: 69.9%, age: 59 ± 11 years, follow-up 217.1 ± 156.4 days), homozygous carriers of a common genetic variant associated with elevated TRPC6 expression were at increased risk of restenosis after coronary stenting (adjusted odds ratio 1.49, 95% confidence interval 1.08-2.05; P = 0.01).CONCLUSIONS : Our study provides a proteomic atlas of the healthy and injured arterial wall that can be used to define novel factors for therapeutic targeting. We present TRPC6 as an actionable target to prevent neointima formation secondary to vascular injury and stent implantation.",
author = "Michael Wierer and Julia Werner and Jana Wobst and Adnan Kastrati and Ganildo Cepele and Redouane Aherrahrou and Sager, {Hendrik B} and Jeanette Erdmann and Martin Dichgans and Veit Flockerzi and Mete Civelek and Alexander Dietrich and Matthias Mann and Heribert Schunkert and Thorsten Kessler",
note = "{\textcopyright} The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.",
year = "2021",
month = apr,
day = "8",
doi = "10.1093/eurheartj/ehab140",
language = "English",
journal = "European Heart Journal",
issn = "0195-668X",
publisher = "Oxford University Press",

}

RIS

TY - JOUR

T1 - A proteomic atlas of the neointima identifies novel druggable targets for preventive therapy

AU - Wierer, Michael

AU - Werner, Julia

AU - Wobst, Jana

AU - Kastrati, Adnan

AU - Cepele, Ganildo

AU - Aherrahrou, Redouane

AU - Sager, Hendrik B

AU - Erdmann, Jeanette

AU - Dichgans, Martin

AU - Flockerzi, Veit

AU - Civelek, Mete

AU - Dietrich, Alexander

AU - Mann, Matthias

AU - Schunkert, Heribert

AU - Kessler, Thorsten

N1 - © The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

PY - 2021/4/8

Y1 - 2021/4/8

N2 - AIMS : In-stent restenosis is a complication after coronary stenting associated with morbidity and mortality. Here, we sought to investigate the molecular processes underlying neointima formation and to identify new treatment and prevention targets.METHODS AND RESULTS : Neointima formation was induced by wire injury in mouse femoral arteries. High-accuracy proteomic measurement of single femoral arteries to a depth of about 5000 proteins revealed massive proteome remodelling, with more than half of all proteins exhibiting expression differences between injured and non-injured vessels. We observed major changes in the composition of the extracellular matrix and cell migration processes. Among the latter, we identified the classical transient receptor potential channel 6 (TRPC6) to drive neointima formation. While Trpc6-/- mice presented reduced neointima formation compared to wild-type mice (1.44 ± 0.39 vs. 2.16 ± 0.48, P = 0.01), activating or repressing TRPC6 in human vascular smooth muscle cells resulted in increased [vehicle 156.9 ± 15.8 vs. 1-oleoyl-2-acetyl-sn-glycerol 179.1 ± 8.07 (103 pixels), P = 0.01] or decreased migratory capacity [vehicle 130.0 ± 26.1 vs. SAR7334 111.4 ± 38.0 (103 pixels), P = 0.04], respectively. In a cohort of individuals with angiographic follow-up (n = 3068, males: 69.9%, age: 59 ± 11 years, follow-up 217.1 ± 156.4 days), homozygous carriers of a common genetic variant associated with elevated TRPC6 expression were at increased risk of restenosis after coronary stenting (adjusted odds ratio 1.49, 95% confidence interval 1.08-2.05; P = 0.01).CONCLUSIONS : Our study provides a proteomic atlas of the healthy and injured arterial wall that can be used to define novel factors for therapeutic targeting. We present TRPC6 as an actionable target to prevent neointima formation secondary to vascular injury and stent implantation.

AB - AIMS : In-stent restenosis is a complication after coronary stenting associated with morbidity and mortality. Here, we sought to investigate the molecular processes underlying neointima formation and to identify new treatment and prevention targets.METHODS AND RESULTS : Neointima formation was induced by wire injury in mouse femoral arteries. High-accuracy proteomic measurement of single femoral arteries to a depth of about 5000 proteins revealed massive proteome remodelling, with more than half of all proteins exhibiting expression differences between injured and non-injured vessels. We observed major changes in the composition of the extracellular matrix and cell migration processes. Among the latter, we identified the classical transient receptor potential channel 6 (TRPC6) to drive neointima formation. While Trpc6-/- mice presented reduced neointima formation compared to wild-type mice (1.44 ± 0.39 vs. 2.16 ± 0.48, P = 0.01), activating or repressing TRPC6 in human vascular smooth muscle cells resulted in increased [vehicle 156.9 ± 15.8 vs. 1-oleoyl-2-acetyl-sn-glycerol 179.1 ± 8.07 (103 pixels), P = 0.01] or decreased migratory capacity [vehicle 130.0 ± 26.1 vs. SAR7334 111.4 ± 38.0 (103 pixels), P = 0.04], respectively. In a cohort of individuals with angiographic follow-up (n = 3068, males: 69.9%, age: 59 ± 11 years, follow-up 217.1 ± 156.4 days), homozygous carriers of a common genetic variant associated with elevated TRPC6 expression were at increased risk of restenosis after coronary stenting (adjusted odds ratio 1.49, 95% confidence interval 1.08-2.05; P = 0.01).CONCLUSIONS : Our study provides a proteomic atlas of the healthy and injured arterial wall that can be used to define novel factors for therapeutic targeting. We present TRPC6 as an actionable target to prevent neointima formation secondary to vascular injury and stent implantation.

U2 - 10.1093/eurheartj/ehab140

DO - 10.1093/eurheartj/ehab140

M3 - Journal article

C2 - 33829256

JO - European Heart Journal

JF - European Heart Journal

SN - 0195-668X

ER -

ID: 259826795