title: Rosiglitazone-induced heart remodelling is associated with enhanced turnover of myofibrillar protein and mTOR activation.
abstract: We investigated cardiac hypertrophy elicited by rosiglitazone treatment at the level of protein synthesis/degradation, mTOR, MAPK and AMPK signalling pathways, cardiac function and aspects of carbohydrate/lipid metabolism. Hearts of rats treated or not with rosiglitazone (15 mg/kg day) for 21 days were evaluated for gene expression, protein synthesis, proteasome and calpain activities, signalling pathways, and function by echocardiography. Rosiglitazone induced eccentric heart hypertrophy associated with increased expression of ANP, BNP, collagen I and III and fibronectin, reduced heart rate and increased stroke volume. Rosiglitazone robustly increased heart glycogen content ( approximately 400%), an effect associated with increases in glycogenin and UDPG-PPL mRNA levels and glucose uptake, and a reduction in glycogen phosphorylase expression and activity. Cardiac triglyceride content, lipoprotein lipase activity and mRNA levels of enzymes involved in fatty acid oxidation were also reduced by the agonist. Rosiglitazone-induced cardiac hypertrophy was associated with an increase in myofibrillar protein content and turnover (increased synthesis and an enhancement of calpain-mediated myofibrillar degradation). In contrast, 26S beta5 chymotryptic proteasome activity and mRNA levels of 20S beta2 and beta5 and 19S RPN 2 proteasome subunits along with the ubiquitin ligases atrogin and CHIP were all reduced by rosiglitazone. These morphological and biochemical changes were associated with marked activation of the key growth-promoting mTOR signalling pathway, whose pharmacological inhibition with rapamycin completely blocked cardiac hypertrophy induced by rosiglitazone. The study demonstrates that both arms of protein balance are involved in rosiglitazone-induced cardiac hypertrophy, and establishes the mTOR pathway as a novel important mediator therein.
authors.affiliation: Department of Anatomy and Physiology, Faculty of Medicine and Laval Hospital Research Center, Laval University, Quebec, Canada G1V 4G5.
authors.forename: William T
authors.initials: WT
authors.lastname: Festuccia
authors.forename: Mathieu
authors.initials: M
authors.lastname: Laplante
authors.forename: Sophie
authors.initials: S
authors.lastname: Brûlé
authors.forename: Vanessa P
authors.initials: VP
authors.lastname: Houde
authors.forename: Adel
authors.initials: A
authors.lastname: Achouba
authors.forename: Dominic
authors.initials: D
authors.lastname: Lachance
authors.forename: Maria L
authors.initials: ML
authors.lastname: Pedrosa
authors.forename: Marcelo E
authors.initials: ME
authors.lastname: Silva
authors.forename: Renata
authors.initials: R
authors.lastname: Guerra-Sá
authors.forename: Jacques
authors.initials: J
authors.lastname: Couet
authors.forename: Marie
authors.initials: M
authors.lastname: Arsenault
authors.forename: André
authors.initials: A
authors.lastname: Marette
authors.forename: Yves
authors.initials: Y
authors.lastname: Deshaies
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism; D004435:Eating / Q000187:drug effects; D004452:Echocardiography; D005964:Glucosyltransferases / Q000235:genetics; D006003:Glycogen / Q000378:metabolism; D024981:Glycogen Phosphorylase / Q000235:genetics; D006006:Glycogen Synthase / Q000235:genetics; D006023:Glycoproteins / Q000235:genetics; D006439:Hemodynamics / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008071:Lipoprotein Lipase / Q000235:genetics; D008297:Male; D009210:Myofibrils / Q000378:metabolism*; D020097:Natriuretic Peptide, Brain / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D058570:TOR Serine-Threonine Kinases; D045162:Thiazolidinediones / Q000494:pharmacology*; D005957:UTP-Glucose-1-Phosphate Uridylyltransferase / Q000235:genetics
chemical_list: D006023:Glycoproteins; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; C051887:glycogenin; D000077154:Rosiglitazone; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; D006003:Glycogen; D005964:Glucosyltransferases; D024981:Glycogen Phosphorylase; D006006:Glycogen Synthase; D011494:Protein Kinases; D058570:TOR Serine-Threonine Kinases; D005957:UTP-Glucose-1-Phosphate Uridylyltransferase; D008071:Lipoprotein Lipase; D046988:Proteasome Endopeptidase Complex