Presentation Information
[II-TKIS-P-1]Genotype dependent alterations in BMPR2 STAT3 signaling linked to late phase right ventricular remodeling
○Lusungu Muchelenganga, Hirofumi Sawada, Mami Takeoka, Yutaka Otobe, Kazunobu Ohya, Naoki Tsuboya, Hiroyuki Ohashi, Noriko Yodoya, Yoshihide Mitani (Department of Pediatrics,Graduate School of Medicine,Mie University,Mie,Japan.)
Keywords:
BMPR2,Pulmonary Arterial Hypertension,STAT3
Background:BMPR2 mutations drive up to 80% of hereditary PAH and are linked to poorer RV outcomes. STAT3, while implicated in pulmonary vascular remodeling, has cardioprotective effects that remain elusive in PAH induced RV failure. We studied time-specific RV responses in wild-type and BMPR2 mutant rats, focusing on BMPR2 and STAT3 signaling
Methods:BMPR2 mutants were generated by CRISPR/Cas9. Four groups were studied: WT control, WT monocrotaline (MCT), BMPR2 mutant control, and BMPR2 mutant MCT. RV function and other assessements were done at days 14, 21, and 28 after MCT.
Results:Subtle increases in mPAP with preserved RV function were noted at day 14 post MCT.Except for BMPR2 MCT rats,phosphorylated and total STAT3 were similar.At day 21,RV function continued to be preserved and similar elevations in RVSP were noted in MCT groups (24.29±0.78 vs 26.38±1.19 mmHg, P=0.38) albeit,TPRI was higher in BMPR2 mutants ( P<0.0001). BMPR2 protein expression increased in WT MCT against BMPR2 mutant MCT rats (P=0.003).By day 28,despite similar elevations in RVSP, RV dysfunction was more severe in BMPR2 mutants compared to their wild type littermates(FAC 33.76±2.65% vs 17.16±2.60%, P=0.0002. BMPR2 and STAT3 protein expression increased exclusively in WT MCT, whereas BMPR2 mutant MCT rats showed greater apoptosis (P<0.0001) and fibrosis (P=0.002).
Conclusion:These findings show, for the first time, time-specific RV adaptation differences with BMPR2 and STAT3 suggesting compensatory roles, while their absence in BMPR2-deficient hearts may impair adaptation
Methods:BMPR2 mutants were generated by CRISPR/Cas9. Four groups were studied: WT control, WT monocrotaline (MCT), BMPR2 mutant control, and BMPR2 mutant MCT. RV function and other assessements were done at days 14, 21, and 28 after MCT.
Results:Subtle increases in mPAP with preserved RV function were noted at day 14 post MCT.Except for BMPR2 MCT rats,phosphorylated and total STAT3 were similar.At day 21,RV function continued to be preserved and similar elevations in RVSP were noted in MCT groups (24.29±0.78 vs 26.38±1.19 mmHg, P=0.38) albeit,TPRI was higher in BMPR2 mutants ( P<0.0001). BMPR2 protein expression increased in WT MCT against BMPR2 mutant MCT rats (P=0.003).By day 28,despite similar elevations in RVSP, RV dysfunction was more severe in BMPR2 mutants compared to their wild type littermates(FAC 33.76±2.65% vs 17.16±2.60%, P=0.0002. BMPR2 and STAT3 protein expression increased exclusively in WT MCT, whereas BMPR2 mutant MCT rats showed greater apoptosis (P<0.0001) and fibrosis (P=0.002).
Conclusion:These findings show, for the first time, time-specific RV adaptation differences with BMPR2 and STAT3 suggesting compensatory roles, while their absence in BMPR2-deficient hearts may impair adaptation