[PPARα attenuates palmitate-induced endoplasmic reticulum stress in human cardiac cells by enhancing AMPK activity].
BACKGROUND
Endoplasmic reticulum (ER) stress has been linked to several cardiovascular diseases, such as atherosclerosis, heart failure and cardiac hypertrophy. ER stress impairs insulin signalling, thus contributing to the development of insulin resistance and diabetes. Since several studies have reported that PPARα may inhibit ER stress, the main aim of this study consisted in investigating whether activation of this nuclear receptor is able to prevent lipid-induced ER stress in cardiac cells, as well as studying the mechanisms involved.


METHODS
A cardiomyocyte cell line of human origin, AC16, was treated with palmitate in the presence or absence of several AMPK and PPARα pharmacological agonists and antagonists. For the in vivo studies, wild-type male mice were fed a standard diet, or a high-fat diet (HFD), for two months. At the end of the experiments, several ER stress markers were assessed in cardiac cells or in the mice hearts, using real-time RT-PCR and Western-blot analyses.


RESULTS
The results demonstrate that both palmitate and the HFD induced ER stress in cardiac cells, since they upregulated the expression (ATF3, BiP/GRP78 and CHOP), splicing (sXBP1), and phosphorylation (IRE-1α and eIF2α) of several ER stress markers. Interestingly, treatment with the PPARα agonist Wy-14,643 prevented an increase in the majority of these ER stress markers in human cardiac cells by means of AMPK activation.


CONCLUSIONS
These data indicate that PPARα activation by Wy-14,643 might be useful to prevent the harmful effects of ER stress and associated cardiovascular diseases in obese patients, and even during diabetic cardiomyopathy, by enhancing AMPK activity.
Departamento de Farmacología y Química Terapéutica, IBUB (Institut de Biomedicina de la Universitat de Barcelona) y CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Facultad de Farmacia, Universitat de Barcelona, Barcelona, España.
Xavier
X
Palomer
Departamento de Farmacología y Química Terapéutica, IBUB (Institut de Biomedicina de la Universitat de Barcelona) y CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Facultad de Farmacia, Universitat de Barcelona, Barcelona, España.
Eva
E
Capdevila-Busquets
Departamento de Farmacología y Química Terapéutica, IBUB (Institut de Biomedicina de la Universitat de Barcelona) y CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Facultad de Farmacia, Universitat de Barcelona, Barcelona, España.
Gerard
G
Garreta
Department of Radiation Oncology, Columbia University, New York, Estados Unidos.
Mercy M
MM
Davidson
Departamento de Farmacología y Química Terapéutica, IBUB (Institut de Biomedicina de la Universitat de Barcelona) y CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Facultad de Farmacia, Universitat de Barcelona, Barcelona, España. Electronic address: mvazquezcarrera@ub.edu.
Manuel
M
Vázquez-Carrera
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000473:pathology*; D047493:PPAR alpha / Q000819:agonists / Q000378:metabolism*; D010168:Palmitates / Q000008:administration & dosage; D011743:Pyrimidines / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction
D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D047493:PPAR alpha; D010168:Palmitates; D011743:Pyrimidines; C006253:pirinixic acid; D055372:AMP-Activated Protein Kinases
5’ AMP-activated protein kinase; Cardiomiocitos; Cardiomiopatía diabética; Cardiomyocyte; Corazón; Diabetic cardiomyopathy; Endoplasmic reticulum stress; Estrés del retículo endoplasmático; Heart; Peroxisome proliferator-activated receptor alpha; Proteína cinasa activada por 5’-AMP; Receptor activado por proliferadores peroxisómicos de tipo α