Functional and molecular determinants of right ventricular response to severe pulmonary hypertension in a large animal model
Functional and molecular determinants of right ventricular response to severe pulmonary hypertension in a large animal model
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DOI：
10.1152/ajpheart.00614.2022
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发表时间：
2023-06-01
影响因子：
4.8
通讯作者：
Stenmark，Kurt R.
中科院分区：
文献类型：
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作者：
Brown，R. Dale;Hunter，Kendall S.;Stenmark，Kurt R.
右心室（RV）衰竭是肺动脉高压（PH）结局的主要决定因素。暴露于缺氧 2 周的小牛会出现严重的 PH，与啮齿类动物不同，缺氧引起的 PH 在该物种中会导致右心衰竭。因此，我们试图检查缺氧引起的 PH 犊牛 RV 的分子和结构变化，假设我们可以识别在严重 PH 发生时补偿生理功能的潜在机制。犊牛暴露在缺氧环境（相当于海拔 4,570 m/15,000 英尺，n= 29）或常氧环境（1,525 m/5,000 英尺，n= 25）中 14 天。通过右心导管插入术和压力容量环评估心肺功能。通过 cDNA 微阵列、实时 PCR、蛋白质组学和免疫化学分析了 RV 重塑的分子和细胞决定因素。缺氧暴露会导致强劲的 PH，增加 RV 收缩性能并保留心输出量，但有证据表明 RV-肺动脉机械耦合失调，如晚期疾病中所见。基因表达分析揭示了与结构重塑、细胞信号传导和生存相关的细胞过程。我们进一步鉴定了与 1) 肥大基因表达和通过 YAP-TAZ 信号转导促进存活的机械转导、2) 细胞外基质 (ECM) 重塑、3) 炎症细胞激活和 4) 血管生成相关的特定基因表达簇。检测到心脏成纤维细胞在 RV 重塑中的潜在转录组特征，富含与细胞运动、组织分化和血管生成相关的功能。蛋白质组学和免疫组织化学分析证实了 RV 肌细胞肥大，以及 RV 间质内 ECM 重塑、炎症细胞激活和内皮细胞增殖的定位。总之，缺氧和血流动力学负荷启动保护性和代偿性 RV 重塑的协调过程，以承受 PH 的进展。新的和值得注意的使用大型动物模型并采用集成血流动力学、转录组、蛋白质组和免疫组织化学分析的综合方法，我们检查了严重 PH 对 RV 的早期（2 周）影响。我们观察到 PH 进展期间的 RV 重塑代表了转录驱动过程的连续体，其中心肌细胞、成纤维细胞、内皮细胞和促重塑巨噬细胞在慢性、严重和进行性压力超负荷期间协调维持生理稳态并保护心肌细胞存活。
Right ventricular (RV) failure is the major determinant of outcome in pulmonary hypertension (PH). Calves exposed to 2-wk hypoxia develop severe PH and unlike rodents, hypoxia-induced PH in this species can lead to right heart failure. We, therefore, sought to examine the molecular and structural changes in the RV in calves with hypoxia-induced PH, hypothesizing that we could identify mechanisms underlying compensated physiological function in the face of developing severe PH. Calves were exposed to 14 days of environmental hypoxia (equivalent to 4,570 m/15,000 ft elevation,n= 29) or ambient normoxia (1,525 m/5,000 ft,n= 25). Cardiopulmonary function was evaluated by right heart catheterization and pressure volume loops. Molecular and cellular determinants of RV remodeling were analyzed by cDNA microarrays, RealTime PCR, proteomics, and immunochemistry. Hypoxic exposure induced robust PH, with increased RV contractile performance and preserved cardiac output, yet evidence of dysregulated RV-pulmonary artery mechanical coupling as seen in advanced disease. Analysis of gene expression revealed cellular processes associated with structural remodeling, cell signaling, and survival. We further identified specific clusters of gene expression associated with1) hypertrophic gene expression and prosurvival mechanotransduction through YAP-TAZ signaling,2) extracellular matrix (ECM) remodeling,3) inflammatory cell activation, and4) angiogenesis. A potential transcriptomic signature of cardiac fibroblasts in RV remodeling was detected, enriched in functions related to cell movement, tissue differentiation, and angiogenesis. Proteomic and immunohistochemical analysis confirmed RV myocyte hypertrophy, together with localization of ECM remodeling, inflammatory cell activation, and endothelial cell proliferation within the RV interstitium. In conclusion, hypoxia and hemodynamic load initiate coordinated processes of protective and compensatory RV remodeling to withstand the progression of PH.NEW & NOTEWORTHYUsing a large animal model and employing a comprehensive approach integrating hemodynamic, transcriptomic, proteomic, and immunohistochemical analyses, we examined the early (2 wk) effects of severe PH on the RV. We observed that RV remodeling during PH progression represents a continuum of transcriptionally driven processes whereby cardiac myocytes, fibroblasts, endothelial cells, and proremodeling macrophages act to coordinately maintain physiological homeostasis and protect myocyte survival during chronic, severe, and progressive pressure overload.