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

Somanshu Banerjee; Jason Hong; Soban Umar

doi:10.3389/fcvm.2022.935423

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

Front Cardiovasc Med. 2022 Sep 9:9:935423. doi: 10.3389/fcvm.2022.935423. eCollection 2022.

Authors

Somanshu Banerjee¹, Jason Hong², Soban Umar¹

Affiliations

¹ Division of Molecular Medicine, Department of Anesthesiology and Perioperative Medicine, Los Angeles, CA, United States.
² Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, United States.

Abstract

Background: 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.

Methods: Male Sprague Dawley rats (250-300 gm; n = 15) were used. Rats received subcutaneous monocrotaline (60 mg/kg; MCT; n = 5) and followed for ~30-days or Sugen (20 mg/kg; Su/Hx; n = 5) followed by hypoxia (10% O₂; 3-weeks) and normoxia (2-weeks). Controls received saline (Control; n = 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).

Results: 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.

Conclusions: 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.

Keywords: Joint Pathway Analysis; Sugen/Hypoxia; monocrotaline; multi-omics; pulmonary hypertension; right ventricular failure; targeted metabolomics.

Abstract

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