title: Modulators of right ventricular apoptosis and contractility in a rat model of pulmonary hypertension.
abstract: OBJECTIVE
  Right ventricular (RV) failure is the major cause of death among patients with pulmonary arterial hypertension (PAH). However, the mechanism of RV failure has not been defined.
  
  
  RESULTS
  This study examined mechanisms and consequences of RV myocyte apoptosis and fibrosis in response to PAH. Rats were injected with SU5416 (vascular endothelial growth factor inhibitor), followed by hypoxia for 3 weeks, and subsequently maintained in normoxia for 2, 5, or 14 weeks (5-, 8-, and 17-week time points after the SU5416 injection, respectively). RV systolic pressure (RVSP) was elevated to >70 mmHg at 5-week time point, and this pressure was sustained thereafter. Significant RV myocyte apoptosis and fibrosis were observed at 8- and 17-week time points. Apoptosis was associated with downregulated Bcl-xL (anti-apoptotic protein), downregulated GATA4 (transcriptional regulator of Bcl-xL), and upregulated p53 (negative regulator of GATA4 gene transcription). PAH-mediated RV apoptosis and fibrosis were attenuated in p53 knock-out rats. Despite the major loss of cardiomyocytes, RV contractility was enhanced, suggesting that the remaining myocytes can perform improved contractile functions. Improved RV contractility is associated with the increased expression of contractile and sarcoplasmic reticulum Ca(2+) uptake proteins. In contrast, the expression of calsequestrin 2 (CSQ2) was downregulated. The siRNA knockdown of CSQ2 improved RV contractility and increased the expression of contractile and Ca(2+) uptake proteins.
  
  
  CONCLUSIONS
  These results suggest that RV decompensation is associated with the death of cardiomyocytes, resulting in fibrosis. However, the remaining myocytes are capable of sustaining RV contractility through the mechanism that involves CSQ2.
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University Medical Center, 3900 Reservoir Road NW, Washington DC 20057, USA.
authors.forename: Makhosazane
authors.initials: M
authors.lastname: Zungu-Edmondson
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University Medical Center, 3900 Reservoir Road NW, Washington DC 20057, USA.
authors.forename: Nataliia V
authors.initials: NV
authors.lastname: Shults
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University Medical Center, 3900 Reservoir Road NW, Washington DC 20057, USA.
authors.forename: Chi-Ming
authors.initials: CM
authors.lastname: Wong
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University Medical Center, 3900 Reservoir Road NW, Washington DC 20057, USA ys82@georgetown.edu.
authors.forename: Yuichiro J
authors.initials: YJ
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D004195:Disease Models, Animal; D006352:Heart Ventricles / Q000378:metabolism / Q000503:physiopathology*; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000378:metabolism; D008297:Male; D011651:Pulmonary Artery / Q000503:physiopathology*; D017207:Rats, Sprague-Dawley; D018497:Ventricular Dysfunction, Right / Q000209:etiology*; D016278:Ventricular Function, Right / Q000502:physiology; D020257:Ventricular Remodeling
keywords: Calsequestrin; Hypertrophy; Pulmonary hypertension; Right ventricle; Right ventricular failure; p53