講演情報
[I-PSY2-1]Translational Impact of Basic Research in Pulmonary Arterial Hypertension
○Marlene Rabinovitch (Department of Pediatrics, Stanford University School of Medicine, California)
キーワード：
pulmonary hypertension、genetics、inflammation
Our group investigates how mutations in specific genes are functionally linked to pulmonary arterial hypertension (PAH). We reported that a heterozygous mutation in BMPR2 leads to endothelial mesenchymal transition, impaired pulmonary arterial (PA) endothelial (EC) regeneration, increased smooth muscle cell (SMC) proliferation, mitochondrial dysfunction, reduced DNA damage repair, decreased elastin fiber assembly and heightened propensity to inflammation both in PAEC and in monocytes. We have since found that in monocytes, reduced BMPR2 causes phosphorylation of KAP1 (TRIM28) resulting in the loss of its methylase activity. Consequently, there is an increase in endogenous retroviral elements (HERVs) causing STAT1 interferon signaling and chronic inflammation. Moreover, the loss of KAP1 methylase activity also prevents inactivation of inflammatory genes on the X chromosome, a feature important in females. Family members that have a mutation in BMPR2 without PAH have mechanisms that improve signaling from the normal BMPR2 receptor that is not mutant. We have also determined that other mutations associated with PAH reduce BMPR2 mediated gene regulation. For example, loss of TBX4, a gene expressed in SMC leads to a reduction in BMP10 and as a consequence a decrease in BMPR2 mediated genes in PAEC, one of which is TMEM100. Replacing TMEM100 in PAEC reverses the adverse consequences of the mutation in TBX4. It other studies we investigated how a mutation in SOX17 causes severe PAH particularly in association with high flow (shear stress) seen in congenital heart defects. We found that the BMPR2 dependent gene TMEM100 is additively reduced by a combination of high shear and loss of SOX17. Thus increasing TMEM100 can potentially reverse PAH resulting from mutations in BMPR2, SOX17 and TBX4 and perhaps other PAH mutant or dysregulated genes.