Comparative analysis of right ventricular metabolic reprogramming in pre-clinical rat models of severe pulmonary hypertension-induced right ventricular failure.
Comparative analysis of right ventricular metabolic reprogramming in pre-clinical rat models of severe pulmonary hypertension-induced right ventricular failure.
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DOI：
10.3389/fcvm.2022.935423
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发表时间：
2022
影响因子：
3.6
通讯作者：
Umar, Soban
中科院分区：
文献类型：
--
作者：
Banerjee, Somanshu;Hong, Jason;Umar, Soban
关键词：
肺动脉高压（PH）导致右心室（RV）肥大和衰竭（RVF）。适应不良 PH 诱导的 RVF (PH-RVF) 代谢基础的确切机制尚未完全阐明。在这里，我们使用靶向代谢组学和多组学对严重 PH-RVF 的 MCT 和 Su/Hx 大鼠模型中的 RV 代谢重编程进行了比较分析。使用雄性 Sprague Dawley 大鼠（250-300 克；n = 15）。大鼠皮下注射野百合碱（60 mg/kg；MCT；n = 5），并持续约 30 天或 Sugen（20 mg/kg；Su/Hx；n = 5），随后缺氧（10% O2；3 周）和常氧（2 周）。对照组接受生理盐水（对照组；n = 5）。进行连续超声心动图评估心肺血流动力学。进行末端 RV 导管插入术以评估 PH。使用 UPLC-MS 对 RV 组织进行靶向代谢组学分析。使用联合通路分析 (JPA) 整合代谢组学和转录组学数据集进行 RV 多组学分析。 MCT 和 Su/Hx 大鼠出现严重的 PH、RV 肥大和失代偿性 RVF。 MCT 和 Su/Hx 大鼠 RV 的靶向代谢组学分别检测到 126 种和 125 种代谢物。 MCT和Su/Hx大鼠的RV中分别有28和24种代谢物发生显着改变，其中包括11种常见代谢物。常见显着上调的代谢物包括天冬氨酸和谷胱甘肽，而下调的代谢物包括磷酸盐、α-酮戊二酸、肌醇、谷氨酰胺、5-氧代脯氨酸、磷酸己糖、肌酸、泛酸和乙酰肉碱。 JPA 强调了糖酵解、脂肪酸代谢、氧化磷酸化、TCA 循环等关键途径的常见基因和代谢物。对 MCT 和 Su/Hx 大鼠 RV 代谢重编程的比较分析揭示了共同且独特的代谢特征，这些特征可能作为 RV 特异性的 PH-RVF 新型治疗靶点。
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; 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). 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.
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影响因子：
20.1
作者：
Doenst T;Nguyen TD;Abel ED
通讯作者：
Abel ED
影响因子：
11.4
作者：
An D;Zeng Q;Zhang P;Ma Z;Zhang H;Liu Z;Li J;Ren H;Xu D
通讯作者：
Xu D
影响因子：
16.6
作者：
Dejana E;Hirschi KK;Simons M
通讯作者：
Simons M
DOI：
10.1016/j.jacbts.2016.06.009
发表时间：
2016-10
期刊：
JACC. Basic to translational science
影响因子：
--
作者：
Diakos NA;Navankasattusas S;Abel ED;Rutter J;McCreath L;Ferrin P;McKellar SH;Miller DV;Park SY;Richardson RS;Deberardinis R;Cox JE;Kfoury AG;Selzman CH;Stehlik J;Fang JC;Li DY;Drakos SG
通讯作者：
Drakos SG
影响因子：
--
作者：
ALLARD, MF;SCHONEKESS, BO;LOPASCHUK, GD
通讯作者：
LOPASCHUK, GD