Project Details
Description
Project Summary:
Growing evidence suggests the link between right ventricular (RV) fibrosis, poor function of the pressure-overloaded
RV, and mortality in pulmonary arterial hypertension (PAH). PAH patients with decompensated RV failure (RVF) have
persistent RV fibrosis even when treated with the conventional therapies for PAH. RVF is the main cause of death in
PAH and maintaining RV function in PAH is associated with improved patient survival. However, there are currently no
available therapies that specifically target RV fibrosis. Therefore, identifying the molecular mechanisms underlying RV
fibrosis in PAH is urgently needed to develop novel therapeutic approaches targeting RVF in PAH.
We recently reported the significant roles of o
xidative stress-sensitive protein kinase
D (PKD) at outer
mitochondrial membrane (OMM) and its substrate dynamin-related protein 1 (DRP1), a mitochondrial fission protein, in
dysregulating CM functions. We also showed that DRP1-mediated mitochondrial fission limits the size of the matrix
cavity, thus causing elevated and sustained mitochondrial Ca2+ (mtCa2+) transient in response to cytosolic Ca2+ elevation.
Using a preclinical rat PAH model with RV hypertrophy, failure, and fibrosis that significant
, we found
PKD activation
and DRP1 phosphorylation occurs specifically
in cardiac fibroblasts (CFs) in the RV (RV-CFs), but not in CMs under
PAH, which subsequently causes an PKD-dependent increase in mitochondrial fission, mitochondrial reactive oxygen
species (mROS), and CF proliferation. Moreover, we found that PKD activation is associated with increased
phosphorylation of a pro-apoptotic protein Bax, which inhibits apoptotic pore formation in the OMM and potentially
contributes to the anti-apoptotic phenotype of RV-CFs in PAH. Lastly, we also found that mtCa2+ uptake via mtCa2+
uniporter (MCU) is required for mROS elevation and subsequent activation of proliferative signaling in CFs. Based on
these findings, we hypothesize that 1) PKD-dependent Bax phosphorylation allows RV-CFs to be resistant to apoptosis
under PAH; 2) PKD-dependent mitochondrial fission limits mtCa2+ and antioxidant capacity by decreasing the size of
the matrix cavity and causing increased mtCa2+ and mROS levels, thus acting as a molecular “switch” for proliferative
signaling for RV-CFs in PAH; and 3) CF-specific inhibition of PKD at the OMM in vivo can be leveraged as a novel
therapy to attenuate cardiac fibrosis in response to stress/injury such as PAH. In Aim 1, we will establish Bax as a novel
PKD substrate in the mitochondria and assess the impact of PKD-dependent Bax phosphorylation on OMM permeability.
To specifically inhibit PKD activity only at the OMM, we will use an OMM-targeted dominant-negative PKD1 (mt-PKD-
DN) that we have newly validated. In Aim 2, we will test whether PKD-dependent enhancement of mitochondrial fission
facilitates RV-CF proliferation via increased mtCa2+ and mROS levels. In Aim 3, we will test the therapeutic potential of
mitochondrial PKD inhibition by mt-PKD-DN in the quiescent CFs before they transform into myofibroblasts by CF-
specifically expressing mt-PKD-DN in a preclinical rat PAH model.
The proposed project is designed to determine the
role of mitochondrial fission, Ca2+, and mROS in RV-CF hyperproliferation and RV fibrosis in PAH, which will lead to
develop a novel strategy (i.e., PKD inhibition) for the management of RV fibrosis and failure in the setting of PAH.
Status | Active |
---|---|
Effective start/end date | 7/1/23 → 6/30/24 |
Funding
- National Heart, Lung, and Blood Institute: $387,500.00
Fingerprint
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.