Modulators of right ventricular apoptosis and contractility in a rat model of pulmonary hypertension

Cardiovascular Research
Makhosazane Zungu-EdmondsonYuichiro J Suzuki

Abstract

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. 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 expres...Continue Reading

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Citations

Nov 27, 2018·Cardiovascular Research·Heather Y Small, Tomasz J Guzik
Feb 27, 2019·Journal of the American Heart Association·Nataliia V ShultsYuichiro J Suzuki
Apr 4, 2019·Pulmonary Circulation·Xianfeng RenWei Dong Gao
Nov 13, 2019·PloS One·Julie Birkmose AxelsenAsger Andersen
Jun 20, 2020·PloS One·Swathi VeerojuTatyana Novoyatleva
Sep 16, 2017·Expert Review of Cardiovascular Therapy·Ming-Sing Si, Richard G Ohye
Sep 29, 2017·Cardiovascular Research·Wouter VandeveldeKarin R Sipido
Aug 12, 2018·Antioxidants·Nataliia V ShultsYuichiro J Suzuki
Aug 5, 2017·American Journal of Physiology. Lung Cellular and Molecular Physiology·Krishna C PenumatsaBarry L Fanburg
Feb 27, 2020·International Journal of Hypertension·Yuejia DingJunping Zhang
Feb 7, 2021·Seminars in Respiratory and Critical Care Medicine·Siddharth Singh, Michael I Lewis
Feb 20, 2021·Experimental Physiology·Ana Filipa SilvaDaniel Moreira-Gonçalves
Aug 28, 2021·American Journal of Physiology. Heart and Circulatory Physiology·Ethan D KwanDaniela Valdez-Jasso

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