IRAG1 Deficient Mice Develop PKG1? Dependent Pulmonary Hypertension.

ABSTRACT: PKGs are serine/threonine kinases. PKG1 has two isoforms-PKG1? and ?. Inositol trisphosphate receptor (IP3R)-associated cGMP-kinase substrate 1 (IRAG1) is a substrate for PKG1?. 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 PKG1? expression. Attenuated PKG1? expression in IRAG1 KO mice further dysregulates other downstream candidates of PKG1? in RV. IRAG1 KO mice develop PH spontaneously. Our results indicate that PKG1? 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.

SUBMITTER: Biswas S 

PROVIDER: S-EPMC7601978 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature