Isoform‐specific Pde3 knockout mice spontaneously develop pulmonary hypertension
Authors: Chen Bernadette , Meng Xiaomei , Xue Jianjing , Liu Yusen , Nelin Leif D 
Published: June 2021

Pulmonary hypertension (PH) is associated with vasoconstriction and vascular remodeling characterized by pulmonary artery smooth muscle cell (PASMC) and microvascular endothelial cell (PMVEC) proliferation and dysfunction. Phosphodiesterase 3 (PDE3), of which there are two isoforms (3A and 3B), hydrolyzes cAMP and cGMP, both critical cyclic nucleotides in cellular function. While both isoforms are present in the pulmonary vasculature, their specific contributions to the regulation of pulmonary vascular tone are unclear. Non‐selective PDE3 inhibitors have been used to treat PH for their vasodilatory effect, presumably by increasing cellular cAMP levels. We hypothesize that isoform‐selective knockout of PDE3 may reveal distinct roles in the regulation of pulmonary vascular tone and/or PH pathogenesis. Adult (8–10 weeks) Pde3a−/− (3A‐KO), Pde3b−/− (3B‐KO), and their respective wild type (WT) mice (3A‐WT, 3B‐WT) were exposed to normoxia or normobaric hypoxia (10% O2) for 28 days. Consistent with previous reports, we found that 3A‐WT and 3B‐WT mice exposed to 10% O2 for 28 days had right ventricular (RV) hypertrophy as evidenced by an increased RV/[left ventricle (LV)+septum (S)] weight ratio relative to mice exposed to 21% O2 [p < 0.001; 0.38 ± 0.01 vs 0.25 ± 0.01 (3A) and 0.35 ± 0.01 vs 0.24 ± 0.01 (3B)]. In hypoxia, 3A‐WT and 3B‐WT mice had elevated pulmonary artery pressures estimated by 2D echocardiography measurements of pulmonary acceleration time/ejection time (PAT/PET) (p < 0.0001; 0.21 ± 0.004 vs 0.29 ± 0.01 (3A) and 0.21 ± 0.01 vs 0.31 ± 0.01 (3B) relative to mice exposed to 21% O2. Interestingly, in normoxia both 3A‐KO (p = 0.012; 0.25 ± 0.004 vs 0.29 ± 0.01 and 3B‐KO (p = 0.023; 0.26 ± 0.01 vs 0.31 ± 0.01) mice had evidence of elevated pulmonary artery pressures relative to their respective WT mice, as evidenced by a lower PAT/PET via echocardiography. Consistent with these results, in normoxia RV/(LV+S) was higher in both 3A‐KO (0.29 ± 0.01 vs 0.25 ± 0.01, p = 0.0008) and 3B‐KO (0.31 ± 0.01 vs 0.24 ± 0.01, p < 0.0001) than in their respective normoxiaexposed WT. Normoxia‐exposed 3B‐KO mice also had elevated right ventricular systolic pressure compared to normoxia‐exposed 3B‐WT (28.9 ± 0.7 mmHg vs 24.2 ± 1.2 mmHg, p = 0.0028). In hypoxia, there was no difference in RV/(LV+S) between 3A‐WT and 3A‐KO mice, although lower estimated pulmonary artery pressures were seen in the 3A‐KO mice (p = 0.0043). Conversely, in hypoxia there was a trend towards higher RV/(LV+S) in the 3B‐KO compared to 3B‐WT mice (p = 0.0532; 0.42 ± 0.02 vs 0.35 vs ± 0.01), but no difference was seen in pulmonary artery pressures between hypoxia‐exposed, 3B‐KO and 3B‐WT mice. Our data suggest a complex and isoform‐specific role of the Pde3 genes in the pathogenesis of PH associated with hypoxia. Furthermore, these data suggest a key role for each of the PDE3 isoforms in the maintenance of the low pulmonary vascular resistance found in normal lungs.Support or Funding Information5K08HL105677‐01A1, R01HL136963‐01A1This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.