Mechanical Load-Dependent Regulation of Gene Expression in Monocrotaline-Induced Right Ventricular Hypertrophy in the Rat

• Published in: Circulation research 2003-08, Vol.93 (3), p.230-237
• Main Authors: Kögler, Harald, Hartmann, Oliver, Leineweber, Kirsten, Nguyen van, Phuc, Schott, Peter, Brodde, Otto-Erich, Hasenfuss, Gerd
• Format: Article
• Language: English
• Subjects: Actin Cytoskeleton - metabolism; Adrenergic beta-Agonists - pharmacology; Animals; Biological and medical sciences; Biomechanical Phenomena; Body Weight - drug effects; Calcium - metabolism; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Calcium-Transporting ATPases - genetics; Calcium-Transporting ATPases - metabolism; Cardiology. Vascular system; Disease Models, Animal; Down-Regulation - drug effects; Gene Expression Regulation; Heart; Heart failure, cardiogenic pulmonary edema, cardiac enlargement; Heart Ventricles - physiopathology; Hypertension, Pulmonary - chemically induced; Hypertension, Pulmonary - complications; Hypertension, Pulmonary - physiopathology; Hypertrophy, Right Ventricular - etiology; Hypertrophy, Right Ventricular - physiopathology; In Vitro Techniques; Isoproterenol - pharmacology; Male; Medical sciences; Monocrotaline; Myocardial Contraction - drug effects; Norepinephrine - blood; Organ Size - drug effects; Rats; Rats, Wistar; RNA, Messenger - metabolism; Ryanodine Receptor Calcium Release Channel - genetics; Ryanodine Receptor Calcium Release Channel - metabolism; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Stress, Mechanical
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000085042.89656.C7

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 Ca-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 Ca-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-Ca 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 Ca-activated tension was enhanced by 64% in permeabilized RV MCT preparations (P =0.013). β-Myosin heavy chain protein was upregulated in MCT RVs (P