Transcriptomic Analysis of Right Ventricular Remodeling in Two Rat Models of Pulmonary Hypertension: Identification and Validation of Epithelial-to-Mesenchymal Transition in Human Right Ventricular Failure
| Autor: | Somanshu Banerjee, John F. Park, Jason S. Hong, Asif Razee, Varina R. Clark, Soban Umar, Tiffany M. Williams, Lou Saddic, Gregory A. Fishbein |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Indoles Medical Physiology Angiogenesis Inhibitors 030204 cardiovascular system & hematology Cardiorespiratory Medicine and Haematology Cardiovascular Transcriptome 0302 clinical medicine Fibrosis pulmonary hypertension Ventricular Dysfunction 80 and over 2.1 Biological and endogenous factors RNA-Seq Aetiology Hypoxia Lung 0303 health sciences Pulmonary Arterial Hypertension Monocrotaline Ventricular Remodeling Middle Aged Right Rv function Cardiology Right ventricular failure Female Cardiology and Cardiovascular Medicine Biotechnology medicine.medical_specialty Epithelial-Mesenchymal Transition Heart Ventricles Rat model Real-Time Polymerase Chain Reaction 03 medical and health sciences Rare Diseases Internal medicine medicine Genetics Animals Humans Pyrroles Epithelial–mesenchymal transition Ventricular remodeling 030304 developmental biology Aged Heart Failure business.industry Animal Gene Expression Profiling fibrosis right ventricular failure medicine.disease Pulmonary hypertension Rats Good Health and Well Being Cardiovascular System & Hematology Disease Models Biochemistry and Cell Biology business |
| Zdroj: | Circulation. Heart failure, vol 14, iss 2 |
| Popis: | Background: Right ventricular (RV) dysfunction is a significant prognostic determinant of morbidity and mortality in pulmonary arterial hypertension (PAH). Despite the importance of RV function in PAH, the underlying molecular mechanisms of RV dysfunction secondary to PAH remain unclear. We aim to identify and compare molecular determinants of RV failure using RNA sequencing of RV tissue from 2 clinically relevant animal models of PAH. Methods: We performed RNA sequencing on RV from rats treated with monocrotaline or Sugen with hypoxia/normoxia. PAH and RV failure were confirmed by catheterization and echocardiography. We validated the RV transcriptome results using quantitative real-time polymerase chain reaction, immunofluorescence, and Western blot. Immunohistochemistry and immunofluorescence were performed on human RV tissue from control (n=3) and PAH-induced RV failure patients (n=5). Results: We identified similar transcriptomic profiles of RV from monocrotaline- and Sugen with hypoxia-induced RV failure. Pathway analysis showed genes enriched in epithelial-to-mesenchymal transition, inflammation, and metabolism. Histological staining of human RV tissue from patients with RV failure secondary to PAH revealed significant RV fibrosis and endothelial-to-mesenchymal transition, as well as elevated cellular communication network factor 2 (top gene implicated in epithelial-to-mesenchymal transition/endothelial-to-mesenchymal transition) expression in perivascular areas compared with normal RV. Conclusions: Transcriptomic signature of RV failure in monocrotaline and Sugen with hypoxia models showed similar gene expressions and biological pathways. We provide translational relevance of this transcriptomic signature using RV from patients with PAH to demonstrate evidence of epithelial-to-mesenchymal transition/endothelial-to-mesenchymal transition and protein expression of cellular communication network factor 2 (CTGF [connective tissue growth factor]). Targeting specific molecular mechanisms responsible for RV failure in monocrotaline and Sugen with hypoxia models may identify novel therapeutic strategies for PAH-associated RV failure. |
| Databáze: | OpenAIRE |
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