PKGs are serine/threonine kinases. PKG1 has two isoforms—PKG1α and β. Inositol trisphosphate receptor (IP₃R)-associated cGMP-kinase substrate 1 (IRAG1) is a substrate for PKG1β. IRAG1 is also known to further interact with IP₃RI, which mediates intracellular Ca²⁺ release. However, the role of IRAG1 in PH is not known. Herein, WT and IRAG1 KO mice were kept under normoxic or hypoxic (10% O₂) conditions for five weeks. Animals were evaluated for echocardiographic variables and went through right heart catheterization. Animals were further sacrificed to prepare lungs and right ventricular (RV) for immunostaining, western blotting, and pulmonary artery smooth muscle cell (PASMC) isolation. IRAG1 is expressed in PASMCs and downregulated under hypoxic conditions. Genetic deletion of IRAG1 leads to RV hypertrophy, increase in RV systolic pressure, and RV dysfunction in mice. Absence of IRAG1 in lung and RV have direct impacts on PKG1β expression. Attenuated PKG1β expression in IRAG1 KO mice further dysregulates other downstream candidates of PKG1β in RV. IRAG1 KO mice develop PH spontaneously. Our results indicate that PKG1β signaling via IRAG1 is essential for the homeostasis of PASMCs and RV. Disturbing this signaling complex by deleting IRAG1 can lead to RV dysfunction and development of PH in mice.

中文翻译：

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IRAG1缺陷小鼠发展为PKG1β依赖性肺动脉高压

PKG是丝氨酸/苏氨酸激酶。PKG1具有两个同工型-PKG1α和β。肌醇三磷酸受体（IP ₃ R）相关的cGMP激酶底物1（IRAG1）是PKG1β的底物。还已知IRAG1与IP ₃ RI进一步相互作用，后者介导细胞内Ca ²⁺释放。但是，IRAG1在PH中的作用尚不清楚。在此，将WT和IRAG1 KO小鼠置于常氧或低氧（10％O ₂）条件持续5周。评价动物的超声心动图变量，并进行右心导管检查。进一步处死动物以准备肺和右心室（RV）进行免疫染色，蛋白质印迹和肺动脉平滑肌细胞（PASMC）分离。IRAG1在PASMC中表达，并在缺氧条件下下调。IRAG1的基因缺失导致小鼠右室肥大，右室收缩压增加和右室功能障碍。肺和右室中IRAG1的缺乏直接影响PKG1β的表达。IRAG1 KO小鼠中PKG1β表达减弱，进一步使RV中PKG1β的其他下游候选者失调。IRAG1 KO小鼠自发发展为PH。我们的结果表明，通过IRAG1传递的PKG1β信号对于PASMC和RV的体内平衡至关重要。