Comparative analysis of right ventricular metabolic reprogramming in pre-clinical rat models of severe pulmonary hypertension-induced right ventricular failure

• Published in: Frontiers in cardiovascular medicine Vol. 9; p. 935423
• Main Authors: Banerjee, Somanshu, Hong, Jason, Umar, Soban
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 09.09.2022
• Subjects: Cardiovascular Medicine; Joint Pathway Analysis; monocrotaline; multi-omics; pulmonary hypertension; right ventricular failure; targeted metabolomics; pulmonary hypertension; monocrotaline; multi-omics; targeted metabolomics; Joint Pathway Analysis; right ventricular failure; Sugen/Hypoxia
• ISSN: 2297-055X; 2297-055X
• DOI: 10.3389/fcvm.2022.935423

Pulmonary hypertension (PH) leads to right ventricular (RV) hypertrophy and failure (RVF). The precise mechanisms of the metabolic basis of maladaptive PH-induced RVF (PH-RVF) are yet to be fully elucidated. Here we performed a comparative analysis of RV-metabolic reprogramming in MCT and Su/Hx rat models of severe PH-RVF using targeted metabolomics and multi-omics. Male Sprague Dawley rats (250-300 gm; = 15) were used. Rats received subcutaneous monocrotaline (60 mg/kg; MCT; = 5) and followed for ~30-days or Sugen (20 mg/kg; Su/Hx; = 5) followed by hypoxia (10% O ; 3-weeks) and normoxia (2-weeks). Controls received saline (Control; = 5). Serial echocardiography was performed to assess cardiopulmonary hemodynamics. Terminal RV-catheterization was performed to assess PH. Targeted metabolomics was performed on RV tissue using UPLC-MS. RV multi-omics analysis was performed integrating metabolomic and transcriptomic datasets using Joint Pathway Analysis (JPA). MCT and Su/Hx rats developed severe PH, RV-hypertrophy and decompensated RVF. Targeted metabolomics of RV of MCT and Su/Hx rats detected 126 and 125 metabolites, respectively. There were 28 and 24 metabolites significantly altered in RV of MCT and Su/Hx rats, respectively, including 11 common metabolites. Common significantly upregulated metabolites included aspartate and GSH, whereas downregulated metabolites included phosphate, α-ketoglutarate, inositol, glutamine, 5-Oxoproline, hexose phosphate, creatine, pantothenic acid and acetylcarnitine. JPA highlighted common genes and metabolites from key pathways such as glycolysis, fatty acid metabolism, oxidative phosphorylation, TCA cycle, etc. Comparative analysis of metabolic reprogramming of RV from MCT and Su/Hx rats reveals common and distinct metabolic signatures which may serve as RV-specific novel therapeutic targets for PH-RVF.