title: The chemical chaperone 4-phenylbutyric acid attenuates pressure-overload cardiac hypertrophy by alleviating endoplasmic reticulum stress.
abstract: Evidence has shown that endoplasmic reticulum stress (ERS) is associated with the pathogenesis of cardiac hypertrophy. The aim of this study was to investigate whether direct alleviation of ER stress by 4-phenylbutyric acid (PBA), a known chemical chaperone drug, could attenuate pressure-overload cardiac hypertrophy in mice. The effects of orally administered PBA (100mg/kg body weight daily for a week) were examined using mice undergoing transverse aortic constriction (TAC-mice), an animal model to produce pressure overload. TAC application for 1 week led to a 1.8-fold increase in the ratio of the heart weight over body weight (HW/BW) and up-regulation of the hypertrophy markers ANF and BNF accompanied by up-regulation of ERS markers (GRP78, p-PERK, and p-elF2α). The oral administration of PBA to the TAC-mice reduced hypertrophy (19%) and severely downregulated the fibrosis-related genes (transforming growth factor-β1, phospho-smad2, and pro-collagen isoforms). We conclude that ERS is induced as a consequence of remodeling during pathological hypertrophy and that PBA may help to relieve ERS and play a protective role against cardiac hypertrophy and possibly heart failure. We suggest PBA as a novel therapeutic agent for cardiac hypertrophy and fibrosis.
authors.affiliation: School of Life Sciences and Systems Biology Research Center, Gwangju Institute of Science and Technology, 123 Cheomdan-gwagiro (1 Oryong-dong), Buk-gu, Gwangju 500-712, Republic of Korea.
authors.forename: Chang Sik
authors.initials: CS
authors.lastname: Park
authors.forename: Hyeseon
authors.initials: H
authors.lastname: Cha
authors.forename: Eun Jeong
authors.initials: EJ
authors.lastname: Kwon
authors.forename: Pradeep Kumar
authors.initials: PK
authors.lastname: Sreenivasaiah
authors.forename: Do Han
authors.initials: DH
authors.lastname: Kim
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001011:Aorta / Q000503:physiopathology; D017209:Apoptosis / Q000187:drug effects; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D006332:Cardiomegaly / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006973:Hypertension / Q000150:complications*; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D010654:Phenylbutyrates / Q000008:administration & dosage*; D011312:Pressure; D014157:Transcription Factors / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects*; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D009320:Atrial Natriuretic Factor; D015415:Biomarkers; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D020097:Natriuretic Peptide, Brain; D010654:Phenylbutyrates; D014157:Transcription Factors; D019892:eIF-2 Kinase; C103652:Elf2 protein, mouse; C000717248:Hspa5 protein, mouse; C075773:4-phenylbutyric acid