title: Regulated inositol-requiring protein 1-dependent decay as a mechanism of corin RNA and protein deficiency in advanced human systolic heart failure.
abstract: BACKGROUND
  The compensatory actions of the endogenous natriuretic peptide system require adequate processing of natriuretic peptide pro‐hormones into biologically active, carboxyl‐terminal fragments. Natriuretic peptide pro‐peptide 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 inositol‐requiring protein 1 (IRE1)‐dependent corin mRNA decay, which would favor a molecular substrate favoring impaired natriuretic peptide pro‐peptide processing.
  
  
  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 X‐box protein 1, a marker for IRE1‐endoribonuclease 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 time‐dependent reductions in corin mRNA. In HL‐1 cells, overexpression of IRE1 activated IRE1 endoribonuclease activity and caused corin mRNA decay, whereas IRE1‐RNA interference with shRNA attenuated corin mRNA decay after induction of endoplasmic reticulum stress with thapsigargin. Pre‐treatment of cells with Actinomycin D to inhibit transcription did not alter the magnitude or time course of thapsigargin‐induced corin mRNA decline, supporting the hypothesis that this was the result of IRE1‐mediated corin mRNA degradation.
  
  
  CONCLUSIONS
  These data support the hypothesis that endoplasmic reticulum stress‐mediated, IRE1‐dependent targeted corin mRNA decay is a mechanism leading to corin mRNA resulting in corresponding corin protein deficiency may contribute to the pathophysiology of impaired natriuretic peptide pro‐hormone processing in humans processing in humans with advanced systolic heart failure.
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Cardiovascular Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA
authors.forename: Rebecca
authors.initials: R
authors.lastname: Lee
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.forename: J Eduardo
authors.initials: JE
authors.lastname: Rame
authors.forename: Leanne E
authors.initials: LE
authors.lastname: Felkin
authors.forename: Paul
authors.initials: P
authors.lastname: Barton
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Dries
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000201:enzymology / Q000473:pathology; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D057809:HEK293 Cells; D006333:Heart Failure / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D051379:Mice; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D020097:Natriuretic Peptide, Brain / Q000235:genetics / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D000071701:Regulatory Factor X Transcription Factors; D012697:Serine Endopeptidases / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D004268:DNA-Binding Proteins; D011498:Protein Precursors; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; C528229:ERN1 protein, human; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; C119812:CORIN protein, human; C485617:Corin protein, mouse; D012697:Serine Endopeptidases