title: Mechanical load-dependent regulation of gene expression in monocrotaline-induced right ventricular hypertrophy in the rat.
abstract: Rats treated with monocrotaline (MCT) develop pulmonary hypertension. Their right ventricles (RVs) exhibit severe pressure overload-induced hypertrophy, whereas the left ventricles (LVs) are normally loaded. In contrast, enhanced neuroendocrine stimulation during the transition to heart failure affects both ventricles. We assessed gene expression levels of Ca2+-regulating proteins in RVs and LVs of control and MCT rats in transition to heart failure to identify biomechanical load-regulated genes. In MCT RVs, both mRNA and protein levels of the Ca2+-ATPase of the sarcoplasmic/endoplasmic reticulum (SERCA2a) were reduced by 36% (P=0.001) and 17% (P=0.016), respectively, compared with control RVs. Phospholamban and ryanodine receptor mRNA levels likewise were reduced (by 27% [P=0.05] and 21% [P=0.011], respectively) in MCT RVs, whereas sarcolemmal Na+-Ca2+ exchanger expression was not altered. MCT LVs exhibited no significant expression changes compared with control LVs. Isometrically contracting MCT intact RV trabeculae showed enhanced baseline force development. Although control RV preparations exhibited a positive force-frequency relationship, MCT RVs showed a negative force-frequency relationship and blunted postrest potentiation. Contractile function of MCT LV trabeculae was normal. Maximum Ca2+-activated tension was enhanced by 64% in permeabilized RV MCT preparations (P=0.013). beta-Myosin heavy chain protein was upregulated in MCT RVs (P<0.001) but unaltered in MCT LVs. Degradation of troponin T was prominent in MCT RVs, a phenomenon not observed in the LV. Enhanced biomechanical load is necessary to induce the gene expression changes associated with the hypertrophic phenotype of the pressure-overloaded RV. Neuroendocrine factors, which equally affect both chambers, are not sufficient to alter the expression of Ca2+-cycling proteins.
authors.affiliation: Georg-August-Universität Göttingen, Abteilung Kardiologie und Pneumologie, Robert-Koch-Str. 40, D-37075 Göttingen, Germany. hkogler@med.uni-goettingen.de
authors.forename: Harald
authors.initials: H
authors.lastname: Kögler
authors.forename: Oliver
authors.initials: O
authors.lastname: Hartmann
authors.forename: Kirsten
authors.initials: K
authors.lastname: Leineweber
authors.forename: Phuc
authors.initials: P
authors.lastname: Nguyen van
authors.forename: Peter
authors.initials: P
authors.lastname: Schott
authors.forename: Otto-Erich
authors.initials: OE
authors.lastname: Brodde
authors.forename: Gerd
authors.initials: G
authors.lastname: Hasenfuss
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001696:Biomechanical Phenomena; D001835:Body Weight / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000503:physiopathology*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology*; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000503:physiopathology*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D016686:Monocrotaline; D009200:Myocardial Contraction / Q000187:drug effects; D009638:Norepinephrine / Q000097:blood; D009929:Organ Size / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D013314:Stress, Mechanical; D000099211:Phospholamban
chemical_list: D000318:Adrenergic beta-Agonists; D002118:Calcium; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D007545:Isoproterenol; D016686:Monocrotaline; D009638:Norepinephrine; D012333:RNA, Messenger; D019837:Ryanodine Receptor Calcium Release Channel; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban