Pulmonary insufficiency (PI) is a common long-term sequel after repair of tetralogy of Fallot, causing progressive right ventricular (RV) dilation and failure. We describe the physiologic and molecular characteristics of the first murine model of RV volume overload. Methods: PI was created by entrapping the pulmonary valve leaflets with sutures. Imaging, catheterization and exercise testing were performed at 1, 3 and 6 months and compared to sham controls. RNA from the RV free wall was hybridized to Agilent whole-genome oligonucleotide microarrays. Results: Volume overload resulted in RV enlargement, decreased RV outflow tract shortening fraction at 1 month followed by normalization at 3 and 6 months (39±2, 44±2 and 41±2 vs. 46±3% in sham), early reversal of E/A ratio followed by pseudonormalization (0.87±0.08, 0.82±0.08 and 0.96±0.08 vs. 1.04±0.03, p<0.05), elevated end diastolic pressure (7.6±0.7, 6.9±0.8 and 7±0.5 vs. 2.7±0.2mmHg, p<0.05) and decreased exercise duration (26±0.4, 26±1 and 22±1.3 vs. 30±1.1 min, p<0.05). Subendocardial RV fibrosis was evident by 1 month. At 1 month, 372 genes were significantly downregulated. Mitochondrial pathways and G-protein coupled receptor signaling were the most represented categories. At 3 months, 434 genes were upregulated and 307 downregulated. While many of the same pathways continued to be downregulated, TNF-α, TGF-β1, p53-signaling, and extracellular matrix (ECM) remodeling transitioned from down- to upregulated. Conclusions: We describe a novel murine model of chronic RV volume overload recapitulating aspects of the clinical disease with gene expression changes suggesting early mitochondrial bioenergetic dysfunction, enhanced TGF-β signaling, ECM remodeling and apoptosis.
"It was shown in ovine studies that pressure and volume overload alter the expression levels of myocyte enhancer factor 2, GATA-4, Nkx2.5, transcriptional enhancer factor 1, and specificity protein (Sp) 1 (44). Another elegant study with pulmonary insufficient mice also exhibited altered expression levels of these transcription factors reflecting changes in transforming growth factor (TGF)-β signaling, ECM remodeling, and apoptosis (45). One of the hallmarks of maladaptive cardiac growth is the α- to β-isotype switch of the major thick filament protein myosin heavy chain (MHC) (α-MHC/β-MHC switch) in cardiomyocytes. "
[Show abstract][Hide abstract] ABSTRACT: Right ventricular dysfunction represents a common problem in patients with congenital heart defects, such as Tetralogy of Fallot or pulmonary arterial hypertension. Patients with congenital heart defects may present with a pressure or volume overloaded right ventricle (RV) in a bi-ventricular heart or in a single ventricular circulation in which the RV serves as systemic ventricle. Both subsets of patients are at risk of developing right ventricular failure. Obtaining functional and morphological imaging data of the right heart is technically more difficult than imaging of the left ventricle. In contrast to findings on mechanisms of left ventricular dysfunction, very little is known about the pathophysiologic alterations of the right heart. The two main causes of right ventricular dysfunction are pressure and/or volume overload of the RV. Until now, there are no appropriate models available analyzing the effects of pressure and/or volume overload on the RV. This review intends to summarize clinical aspects mainly focusing on the current research in this field. In future, there will be increasing attention to individual care of patients with right heart diseases. Hence, further investigations are essential for understanding the right ventricular pathobiology.
Frontiers in Pediatrics 11/2013; 1:37. DOI:10.3389/fped.2013.00037
[Show abstract][Hide abstract] ABSTRACT: Background: Alterations in the ubiquitin-proteasome system (UPS) have been described in left ventricular hypertrophy and failure, although results have been inconsistent. The role of the UPS in right ventricular hypertrophy (RVH) and failure (RVF) is unknown. Given the greater percent increase in RV mass associated with RV afterload stress, as present in many congenital heart lesions, we hypothesized that alterations in the UPS could play an important role in RVH/RVF. Methods and Results: UPS expression and activity were measured in the RV from mice with RVH/RVF secondary to pulmonary artery constriction (PAC). Epoxomicin and MG132 were used to inhibit the proteasome, and overexpression of the 11S PA28α subunit was used to activate the proteasome. PAC mice developed RVH (109.3% increase in RV weight to body weight, RVW/BW), RV dilation with septal shift, RV dysfunction and clinical RVF. Proteasomal function (26S β5 chymotrypsin-like activity) was decreased 26% (p<0.05). Protein expression of 19S subunit Rpt5 (p<0.05), UCHL1 deubiquitinase (p<0.0001), and Smurf1 E3 ubiquitin ligase (p<0.01) were increased, as were polyubiquitinated proteins (p<0.05) and free-ubiquitins (p=0.05). Pro-apoptotic Bax was increased (p<0.0001), while anti-apoptotic Bcl-2 decreased (p<0.05) resulting in a 6-fold increase in Bax/Bcl-2 ratio. Proteasomal inhibition did not accelerate RVF. However, proteasome enhancement by cardiac-specific proteasome overexpression partially improved survival. Conclusions: Proteasome activity is decreased in RVH/RVF, associated with upregulation of key UPS regulators and pro-apoptotic signaling. Enhancement of proteasome function partially attenuates RVF suggesting that UPS dysfunction contributes to RVF.
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