PERK participates in cardiac valve development via fatty acid oxidation and endocardial-mesenchymal transformation.

Scientific Reports
Takashi ShimizuYouichiro Wada

Abstract

Protein kinase R-like endoplasmic reticulum kinase (PERK) is one of the endoplasmic reticulum (ER) stress sensors. PERK loss-of-function mutations are known to cause Wolcott-Rallison syndrome. This disease is characterized by early-onset diabetes mellitus, skeletal dysplasia, and cardiac valve malformation. To understand the role of PERK in valve formation in vivo, we used an endothelial-specific PERK conditional knockout mice as well as in vitro PERK inhibition assays. We used ProteoStat dyes to visualize the accumulation of misfolded proteins in the endocardial cushion and valve mesenchymal cells (VMCs). Then, VMCs were isolated from E12.5 fetal mice, by fluorescence assisted cell sorting. Proteomic analysis of PERK-deleted VMCs identified the suppression of proteins related to fatty acid oxidation (FAO), especially carnitine palmitoyltransferase II (CPT2). CPT2 is a critical regulator of endocardial-mesenchymal transformation (EndoMT); however how TGF-β downstream signaling controls CPT2 expression remains unclear. Here, we showed that PERK inhibition suppressed, not only EndoMT but also CPT2 protein expression in human umbilical vein endothelial cells (HUVECs) under TGF-β1 stimulation. As a result, PERK inhibition suppresse...Continue Reading

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Citations

Jun 8, 2021·Frontiers in Cell and Developmental Biology·Guizhen ZhaoJifeng Zhang

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Methods Mentioned

BETA
flow cytometry
FACS
Fluorescence-assisted cell sorting
ELISA
PCR
fluorescence-activated cell sorting
protein

Software Mentioned

Proteome
Scaffold
Ingenuity Pathway Analysis ( IPA )
ProteoStat
Mascot
IPA
Graph Pad Prism8
Ingenuity Pathway Analysis software ( IPA
Xcalibur

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