Inactivation of catalytic and non-catalytic PI3 kinase gamma functions enhances hypoxia-induced pulmonary hypertension in mice

Abstract Rationale Pulmonary hypertension (PH) is a pulmonary vascular disease characterised by chronically elevated arterial mean pressure, increased resistance and right ventricular (RV) dysfunction hypertrophy. The pathogenesis includes vasoconstriction of vessels remodelling. Phosphatidylinositol 3'-kinase γ (PI3Kγ) highly expressed in leukocytes, endothelial cells (EC) cardiomyocytes, which are involved the PH. catalytic function PI3Kγ has been shown to be associated with numerous processes that potentially important for both remodelling maladaptive cardiac hypertrophy, including leukocyte recruitment cell proliferation survival. However, inhibition non-catalytic results reduced nitric oxide (NO) production NO synthase (eNOS), may lead resistance. Therefore, aim our study was investigate role functions Methods importance PH analysed vivo using hypoxia-induced mouse model (21 days at 10% O2 hypoxia (HOX)). knockout mice (PI3Kγ−/−), as well expressing catalytically inactive form (PI3KγKD/KD) were investigated. To specifically inhibit PI3Kγ, C57BL/6N treated blocking peptide via intratracheal instillation studied same model. Subsequently, systolic pressure (RVSP) measured Millar catheter inserted jugular vein. In vitro, western blotting used phosphorylation eNOS (Ser1177) ECs from wild type (WT), PI3Kγ−/− PI3KγKD/KD mice. Results showed significantly RVSP after three weeks compared WT controls (HOX 34.16±3.47mmHg vs. HOX 37.04±2.43mmHg; p=0.005; n≥7). A significant increase also detected peptide-treated 34.67±2.02mmHg 37.95±1.39mmHg; p=0.023; n≥5 vehicle 34.19±2.74mmHg 37.61±2.46mmHg; p=0.011; n≥9). Heart rate, systemic blood remained unchanged. Under normoxic conditions, no difference between groups could measured. Interestingly, blot stimulation fetal calf serum PI3KγKD/KD. Conclusion These show blunting do not prevent PH, but conversely enhance elevation RVSP. this context, play crucial role, leading vasoconstriction. Additional studies required evaluate underlying mechanisms detail. Funding Acknowledgement Type funding sources: Foundation. Main source(s): DFG Deutsche Forschungsgemeinschaft