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Lipophilic And Hydrophilic Statins Differentially Modulate Endoplasmic Reticulum Stress Response In Cardiac Myocytes
Author(s) -
Godoy Joseph C.,
Asfaw Elizabeth K.,
Alvarez Erika A.,
Dalton Nancy D.,
Niesman Ingrid,
Patel Hemal H.,
Zemljic-Harpf Alice E.
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.714.5
Subject(s) - atorvastatin , endoplasmic reticulum , unfolded protein response , pravastatin , hmg coa reductase , chop , chemistry , atf6 , myocyte , mevalonic acid , pharmacology , statin , endocrinology , medicine , microbiology and biotechnology , reductase , cholesterol , biochemistry , biology , enzyme
Statins inhibit HMG‐CoA reductase, target mevalonic acid synthesis, and limit cholesterol biosynthesis. HMG‐CoA reductase is expressed in the membrane of the endoplasmic reticulum (ER). Statins are prescribed to prevent cardiovascular events. In cultured neonatal mouse cardiac myocytes the lipophilic statin atorvastatin and the hydrophilic statin pravastatin both up‐regulated PDI, indicating unfolded protein response (UPR) meant to relieve ER stress. Only atorvastatin increased ER stress, growth arrest, and induced apoptosis via induction of CHOP, Puma, active Caspase‐3 and PARP. Dose‐dependent release of LDH was only observed in atorvastatin treated cells (1–10 μM). Hearts of mice treated with atorvastatin (5mg/kg/day for 7 months) showed protein aggresomes and autophagosomes when compared to vehicle treated controls. While atorvastatin changed mitochondrial ultrastructure, no differences in cardiac function, exercise ability or creatine kinase levels were found. We show differential activation of ER stress by atorvastatin and pravastatin in cardiac myocytes. Our results provide a novel mechanism through which specific statins therapeutically modulate the balance of UPR/ER stress responses thereby possibly influencing cardiac remodeling.