Combination Therapy with STAT3 Inhibitor Enhances SERCA2a-Induced BMPR2 Expression and Inhibits Pulmonary Arterial Hypertension.
Combination Therapy with STAT3 Inhibitor Enhances SERCA2a-Induced BMPR2 Expression and Inhibits Pulmonary Arterial Hypertension.
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与 STAT3 抑制剂的联合治疗可增强 SERCA2a 诱导的 BMPR2 表达并抑制肺动脉高压。
DOI：
10.3390/ijms22179105
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发表时间：
2021-08-24
影响因子：
5.6
通讯作者：
Hadri L
中科院分区：
文献类型：
--
作者：
Bisserier M;Katz MG;Bueno-Beti C;Brojakowska A;Zhang S;Gubara S;Kohlbrenner E;Fazal S;Fargnoli A;Dorfmuller P;Humbert M;Hata A;Goukassian DA;Sassi Y;Hadri L
肺动脉高压（PAH）是一种以远端肺动脉（PA）进行性阻塞为特征的破坏性肺部疾病。肺动脉平滑肌细胞（PASMC）和内皮细胞（PAEC）的结构和功能改变有助于PA壁重构和血管阻力，这可能导致适应不良的右心室（RV）衰竭，并最终导致死亡。在这里，我们发现PAH患者肺样本中肌质/内质网Ca 2 + ATP酶2a（SERCA 2a）表达降低与骨形态发生蛋白受体2（BMPR 2）下调和信号转导和转录激活因子3（STAT 3）激活相关。我们的结果表明SERCA 2a的抗增殖特性是通过STAT 3/BMPR 2途径介导的。在分子水平上，共过表达SERCA 2a和BMPR 2的PASMC的转录组分析鉴定出STAT 3是最高度调节的转录因子之一。使用特异性siRNA和有效的药理学STAT 3抑制剂（STAT 3 i，HJC 0152），我们发现SERCA 2a通过抑制PASMCs和PAECs中的STAT 3活性来增强BMPR 2表达。在体内，我们使用了单侧左肺切除术联合野百合碱（PNT/MCT）诱导的重度PAH的有效模型，以进一步评估使用腺相关病毒（AAV）技术和STAT 3 i的单药和联合治疗的治疗潜力。我们发现，单独的编码SERCA 2或BMPR 2或STAT 3 i的AAV 1的血管内递送足以降低平均PA压力和血管重塑，同时改善RV收缩压、RV射血分数和心脏重塑。有趣的是，我们发现AAV1.hSERCA2a与AAV1.hBMPR2或STAT 3 i的联合治疗增强了SERCA 2a的有益作用。最后，我们使用心脏磁共振成像来测量RV功能，发现单独使用AAV1.hSERCA2a或与STAT 3 i联合使用的治疗显著抑制了PNT/MCT诱导的PAH中的RV结构和功能变化。总之，我们的研究表明，使用SERCA 2a基因转移与STAT 3抑制剂的联合治疗可以代表一种新的有希望的治疗替代方案，以抑制PAH并通过限制STAT 3活性来恢复BMPR 2表达。
Pulmonary arterial hypertension (PAH) is a devastating lung disease characterized by the progressive obstruction of the distal pulmonary arteries (PA). Structural and functional alteration of pulmonary artery smooth muscle cells (PASMC) and endothelial cells (PAEC) contributes to PA wall remodeling and vascular resistance, which may lead to maladaptive right ventricular (RV) failure and, ultimately, death. Here, we found that decreased expression of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) in the lung samples of PAH patients was associated with the down-regulation of bone morphogenetic protein receptor type 2 (BMPR2) and the activation of signal transducer and activator of transcription 3 (STAT3). Our results showed that the antiproliferative properties of SERCA2a are mediated through the STAT3/BMPR2 pathway. At the molecular level, transcriptome analysis of PASMCs co-overexpressing SERCA2a and BMPR2 identified STAT3 amongst the most highly regulated transcription factors. Using a specific siRNA and a potent pharmacological STAT3 inhibitor (STAT3i, HJC0152), we found that SERCA2a potentiated BMPR2 expression by repressing STAT3 activity in PASMCs and PAECs. In vivo, we used a validated and efficient model of severe PAH induced by unilateral left pneumonectomy combined with monocrotaline (PNT/MCT) to further evaluate the therapeutic potential of single and combination therapies using adeno-associated virus (AAV) technology and a STAT3i. We found that intratracheal delivery of AAV1 encoding SERCA2 or BMPR2 alone or STAT3i was sufficient to reduce the mean PA pressure and vascular remodeling while improving RV systolic pressures, RV ejection fraction, and cardiac remodeling. Interestingly, we found that combined therapy of AAV1.hSERCA2a with AAV1.hBMPR2 or STAT3i enhanced the beneficial effects of SERCA2a. Finally, we used cardiac magnetic resonance imaging to measure RV function and found that therapies using AAV1.hSERCA2a alone or combined with STAT3i significantly inhibited RV structural and functional changes in PNT/MCT-induced PAH. In conclusion, our study demonstrated that combination therapies using SERCA2a gene transfer with a STAT3 inhibitor could represent a new promising therapeutic alternative to inhibit PAH and to restore BMPR2 expression by limiting STAT3 activity.
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影响因子：
5.6
作者：
Andruska A;Spiekerkoetter E
通讯作者：
Spiekerkoetter E
影响因子：
37.8
作者：
Bisserier, Malik;Berthouze-Duquesnes, Magali;Lezoualc'h, Frank
通讯作者：
Lezoualc'h, Frank
影响因子：
6.2
作者：
HecklOstreicher, B;Wosnik, A;Kirschfink, M
通讯作者：
Kirschfink, M
影响因子：
37.8
作者：
Hadri L;Kratlian RG;Benard L;Maron BA;Dorfmüller P;Ladage D;Guignabert C;Ishikawa K;Aguero J;Ibanez B;Turnbull IC;Kohlbrenner E;Liang L;Zsebo K;Humbert M;Hulot JS;Kawase Y;Hajjar RJ;Leopold JA
通讯作者：
Leopold JA
影响因子：
2.3
作者：
Chamberlain K;Riyad JM;Weber T
通讯作者：
Weber T