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@article{Lee:2014:10.1161/JAHA.114.001104,
author = {Lee, R and Xu, B and Rame, JE and Felkin, LE and Barton, P and Dries, DL},
doi = {10.1161/JAHA.114.001104},
journal = {Journal of the American Heart Association},
title = {Regulated InositolRequiring Protein 1Dependent Decay as a Mechanism of Corin RNA and Protein Deficiency in Advanced Human Systolic Heart Failure},
url = {http://dx.doi.org/10.1161/JAHA.114.001104},
volume = {3},
year = {2014}
}

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TY  - JOUR
AB  - BACKGROUND: The compensatory actions of the endogenous natriuretic peptide system require adequate processing of natriuretic peptide prohormones into biologically active, carboxylterminal fragments. Natriuretic peptide propeptide processing is accomplished by corin, a transmembrane serine protease expressed by cardiomyocytes. Brain natriuretic peptide (BNP) processing is inadequate in advanced heart failure and is independently associated with adverse outcomes; however, the molecular mechanisms causing impaired BNP processing are not understood. We hypothesized that the development of endoplasmic reticulum stress in cardiomyocytes in advanced heart failure triggers inositolrequiring protein 1 (IRE1)dependent corin mRNA decay, which would favor a molecular substrate favoring impaired natriuretic peptide propeptide processing. METHODS AND RESULTS: Two independent samples of hearts obtained from patients with advanced heart failure at transplant demonstrated that corin RNA was reduced as Atrial natriuretic peptide (ANP)/BNP RNA increased. Increases in spliced Xbox protein 1, a marker for IRE1endoribonuclease activity, were associated with decreased corin RNA. Moreover, ≈50% of the hearts demonstrated significant reductions in corin RNA and protein as compared to the nonfailing control sample. In vitro experiments demonstrated that induction of endoplasmic reticulum stress in cultured cardiomyocytes with thapsigargin activated IRE1's endoribonuclease activity and timedependent reductions in corin mRNA. In HL1 cells, overexpression of IRE1 activated IRE1 endoribonuclease activity and caused corin mRNA decay, whereas IRE1RNA interference with shRNA attenuated corin mRNA decay after induction of endoplasmic reticulum stress with thapsigargin. Pretreatment of cells with Actinomycin D to inhibit transcription did not alter the magnitude or time course of thapsigargininduced corin mRNA decline, supporting the hypothesis that this was the result of IRE1medi
AU  - Lee,R
AU  - Xu,B
AU  - Rame,JE
AU  - Felkin,LE
AU  - Barton,P
AU  - Dries,DL
DO  - 10.1161/JAHA.114.001104
PY  - 2014///
SN  - 2047-9980
TI  - Regulated InositolRequiring Protein 1Dependent Decay as a Mechanism of Corin RNA and Protein Deficiency in Advanced Human Systolic Heart Failure
T2  - Journal of the American Heart Association
UR  - http://dx.doi.org/10.1161/JAHA.114.001104
UR  - http://hdl.handle.net/10044/1/34472
VL  - 3
ER  -

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