Sotatercept analog suppresses inflammation to reverse experimental pulmonary arterial hypertension.
Sotatercept analog suppresses inflammation to reverse experimental pulmonary arterial hypertension.
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DOI：
10.1038/s41598-022-11435-x
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发表时间：
2022-05-12
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
--
作者：
Sotatercept是一种激活素受体型IIA-Fc （ActRIIA-Fc）融合蛋白，通过选择性捕获激活素和生长分化因子改善肺动脉高压（PAH）患者的心肺功能。然而，ActRIIA-Fc作用的细胞和分子机制尚不完全清楚。在这里，我们通过全基因组表达谱确定，严重血管闭塞性PAH缺氧大鼠模型的肺部炎症和免疫反应显著上调，与PAH患者观察到的特征一致。用actriia - fc治疗，而不是血管扩张剂治疗，显著逆转了患病啮齿动物肺部的促炎和增殖基因表达谱，并使巨噬细胞浸润正常化。此外，在Bmpr2单倍体不足的小鼠（遗传性PAH模型）缺氧时，ActRIIA-Fc使肺巨噬细胞浸润正常化，并纠正心肺结构和功能。ActRIIA-Fc的三种高亲和力配体分别在体外诱导巨噬细胞活化，它们在PAH大鼠中的联合免疫中和产生的心肺益处与ActRIIA-Fc诱导的效果相当。在PAH的互补实验和遗传模型中，我们的结果揭示了ActRIIA-Fc的治疗性抗炎活性，以及它对血管细胞类型的已知抗增殖作用，可能是sotaterept作为单一疗法或当前PAH治疗的附加疗法的临床活性基础。
Sotatercept is an activin receptor type IIA-Fc (ActRIIA-Fc) fusion protein that improves cardiopulmonary function in patients with pulmonary arterial hypertension (PAH) by selectively trapping activins and growth differentiation factors. However, the cellular and molecular mechanisms of ActRIIA-Fc action are incompletely understood. Here, we determined through genome-wide expression profiling that inflammatory and immune responses are prominently upregulated in the lungs of a Sugen-hypoxia rat model of severe angio-obliterative PAH, concordant with profiles observed in PAH patients. Therapeutic treatment with ActRIIA-Fc—but not with a vasodilator—strikingly reversed proinflammatory and proliferative gene expression profiles and normalized macrophage infiltration in diseased rodent lungs. Furthermore, ActRIIA-Fc normalized pulmonary macrophage infiltration and corrected cardiopulmonary structure and function in Bmpr2 haploinsufficient mice subjected to hypoxia, a model of heritable PAH. Three high-affinity ligands of ActRIIA-Fc each induced macrophage activation in vitro, and their combined immunoneutralization in PAH rats produced cardiopulmonary benefits comparable to those elicited by ActRIIA-Fc. Our results in complementary experimental and genetic models of PAH reveal therapeutic anti-inflammatory activities of ActRIIA-Fc that, together with its known anti-proliferative effects on vascular cell types, could underlie clinical activity of sotatercept as either monotherapy or add-on to current PAH therapies.
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影响因子：
32.4
作者：
Fielding, Ceri A.;Jones, Gareth W.;McLoughlin, Rachel M.;McLeod, Louise;Hammond, Victoria J.;Uceda, Javier;Williams, Anwen S.;Lambie, Mark;Foster, Thomas L.;Liao, Chia-Te;Rice, Christopher M.;Greenhill, Claire J.;Colmont, Chantal S.;Hams, Emily;Coles, Barbara;Kift-Morgan, Ann;Newton, Zarabeth;Craig, Katherine J.;Williams, John D.;Williams, Geraint T.;Davies, Simon J.;Humphreys, Ian R.;O'Donnell, Valerie B.;Taylor, Philip R.;Jenkins, Brendan J.;Topley, Nicholas;Jones, Simon A.
通讯作者：
Jones, Simon A.
DOI：
10.1164/rccm.201607-1515pp
发表时间：
2017-03-01
影响因子：
24.7
作者：
Bonnet, Sebastien;Provencher, Steeve;Humbert, Marc
通讯作者：
Humbert, Marc
影响因子：
9.8
作者：
Hiepen, Christian;Jatzlau, Jerome;Knaus, Petra
通讯作者：
Knaus, Petra
影响因子：
4.4
作者：
Gawa, Kenji;Funaba, Masayuki;Tsujimoto, Masafumi
通讯作者：
Tsujimoto, Masafumi
影响因子：
8
作者：
Duan M;Steinfort DP;Smallwood D;Hew M;Chen W;Ernst M;Irving LB;Anderson GP;Hibbs ML
通讯作者：
Hibbs ML