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Mitochondrial Fission, Calcium, ROS in Right Ventricular Fibrosis

Award Number: R01HL160699
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Mitochondrial Fission, Calcium, ROS in Right Ventricular Fibrosis - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $375,000 )
2026	2026	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Cardiovascular Diseases Research	005	4	8/5/2026	NON-COMPETING CONTINUATION	$375,000
2026	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Cardiovascular Diseases Research	001	2	2/6/2026	NON-COMPETING CONTINUATION	$0
2026	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Cardiovascular Diseases Research	000	2	1/22/2026	NON-COMPETING CONTINUATION	-$370,913
2026	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Cardiovascular Diseases Research	004	2	5/14/2026	NON-COMPETING CONTINUATION	$372,967
2026	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Cardiovascular Diseases Research	002	2	3/12/2026	NON-COMPETING CONTINUATION	-$494
2026	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Cardiovascular Diseases Research	003	2	4/8/2026	NON-COMPETING CONTINUATION	-$1,560
														Subtotal = $375,000

Issue Date FY: 2025 ( Subtotal = $375,000 )
2025	2025	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Cardiovascular Diseases Research	001	3	9/18/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$375,000
2025	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Cardiovascular Diseases Research	000	2	9/18/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $375,000

Issue Date FY: 2024 ( Subtotal = $387,500 )
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cardiovascular Diseases Research	000	2	6/17/2024	NON-COMPETING CONTINUATION	$387,500
														Subtotal = $387,500

Issue Date FY: 2023 ( Subtotal = $387,500 )
2023	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cardiovascular Diseases Research	000	1	6/30/2023	NEW	$387,500
														Subtotal = $387,500

Grand Total All Awards = $1,525,000

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Mitochondrial Fission, Calcium, ROS in Right Ventricular Fibrosis

Award Number: R01HL160699

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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