# Sub-cellular Targeting of Endothelial ROS in Myocardial Ischemia

> **NIH NIH R56** · RHODE ISLAND HOSPITAL · 2022 · $613,235

## Abstract

renewal application is based on the novel findings that reduction in mito-ROS, using genetic
manipulation and/or nanoparticle drugs, improve survival and proliferation of coronary EC and help recover
cardiac function in a post-myocardial infarct (MI) animal model and human atrial tissue. Preliminary findings
in the current application demonstrate that reduction of mito-ROS using transgene (MnSOD) and nanodrugs
(JP4-039, XJB5-131) induce mitochondrial complex I biogenesis (proteomic and phosphoproteomic data)
and oxidative phosphorylation (Ox-Phos) in EC resulting in coronary angiogenesis cardiac function recovery
in post-MI heart.
This innovative
EC, like most tumor cells, utilizes anerobic glycolysis as a major (85%) source of ATP
Thus, the shift from less-
efficient energy production system glycolysis (2 ATP/glucose molecule), to a more efficient Ox-Phos (34-36
ATP/glucose) may provide critical energy support to EC needed during ischemia (low glucose, oxygen). Here,
we propose to examine a novel overarching hypothesis that modulation of mito-ROS improves
production, while EC mitochondria are mostly involved in dNTP biosynthesis.
Δψm and
‘super-complex’ (SC) formation resulting in efficient electron transport chain (ETC) and Ox-Phos-mediated
ATP generation in EC during ischemia. This shift from
glycolysis to a more efficient mitochondrial Ox-Phos
may provide resilience/survival to coronary EC during ‘energy crisis’ in myocardial ischemia.
The therapeutic
benefit of intervening on subcellular ROS level will be best realized by specific down regulation of mito-ROS
in ECs that have been exposed to ischemia/hypoxia. This hypothesis will be fully tested in vivo using our
novel EC-specific transgenic MnSOD (SOD-OE; mitochondrial antioxidant) animals and supported using
mitochondria-specific nitroxide and nanoparticle antioxidant in large animal model (swine) and in coronary
vessels from CVD patients undergoing cardiac surgery. We propose three Specific Aims. Aim 1: Elucidate
the molecular mechanisms by which modulation of mitochondrial ROS protect coronary EC from oxidative
stress and induce coronary angiogenesis during myocardial ischemia. Using SOD-VE transgenic animals
and myocardial infarct-mimicking (LAD ligation) surgeries, Δψm, super-complex (SC) formation, oxygen
consumption rate (OCR) versus extracellular acidification rate (ECAR), ATP synthesis, will be assessed. Aim
2: Determine the effects mitochondria-targeted MnSOD-mimetic (JP4-039, XJB-5-131) nanoparticles on
post-infarct vessel density and recovery of cardiac function in mice and on chronic myocardial ischemia in
large animals (swine). Aim 3: Elucidate the molecular mechanisms by which mitochondrial antioxidant
nanoparticles (JP4-039/XJB-5-131) improve angiogenic potential of human coronary vessels (from cardiac
surgery patients) ex vivo. This study using unique animal models, human atrial tissue, and mitochondria-
specific antioxidant will provide novel insights into the mechanisms by...

## Key facts

- **NIH application ID:** 10705336
- **Project number:** 2R56HL133624-05
- **Recipient organization:** RHODE ISLAND HOSPITAL
- **Principal Investigator:** Ruhul Abid
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $613,235
- **Award type:** 2
- **Project period:** 2017-08-10 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10705336

## Citation

> US National Institutes of Health, RePORTER application 10705336, Sub-cellular Targeting of Endothelial ROS in Myocardial Ischemia (2R56HL133624-05). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10705336. Licensed CC0.

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