# Anaplerotic reprogramming of endothelial cells in pulmonary hypertension.

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2020 · $383,750

## Abstract

PROJECT SUMMARY
Pulmonary arterial hypertension (PH) is a fatal disease with uncontrolled pulmonary vascular cell
proliferation. Excessive endothelial cell (EC) growth leads to the formation of plexiform lesions, which are
a characteristic cancer-like change within pulmonary arteries of patients with PH. The increased
oxidative stress in lungs of patients with PH leads to the reaction of superoxide with NO. This results in
the formation of highly reactive peroxynitrite (ONOO-) which, in turn, can produce nitro-tyrosine
modifications in proteins. Lung tissues from patients with PH have an increased level of protein nitration.
Our recently published work indicates that the nitration of tyrosine 350 residue in Akt leads to the
sustained activation of Akt signaling. The activation of Akt is a well described cell survival and stress
response but Akt activation is tightly regulated by the regulatory kinases/phosphatases (PTEN, PI3K,
PDK1 and mTOR) that control Akt activity and ensuring that it is only temporarily active. Pathological
activation of the Akt pathway has been implicated in various cancers. We hypothesize that in PH,
nitration of Akt increases translocation of eNOS to mitochondria, which downregulates oxidative
phosphorylation and activates Pyruvate Carboxylase (PC), which upregulates anaplerosis. This
activation of anaplerosis then leads to pathological hyper-proliferation of endothelial cells (EC) and
plexiform lesion formation in PH. Further, we propose to target pathological Akt signaling using an Akt-
binding peptide conjugated with an antioxidant (shielding peptide) that only affects nitration mediated Akt
activation. We will test these hypotheses in the following Aims: AIM 1: To elucidate the role of nitration
(Y350) mediated Akt activation in activation of anaplerosis in EC. AIM 2: To determine whether inhibition
of Akt nitration disrupts formation of the apoptosis resistant and proliferative EC phenotype. AIM 3: To
examine the effect of Akt shielding peptide on EC hyper-proliferation in the SU5416/hypoxia PH models.

## Key facts

- **NIH application ID:** 9955307
- **Project number:** 5R01HL132918-05
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Ruslan Rafikov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $383,750
- **Award type:** 5
- **Project period:** 2016-08-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9955307

## Citation

> US National Institutes of Health, RePORTER application 9955307, Anaplerotic reprogramming of endothelial cells in pulmonary hypertension. (5R01HL132918-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9955307. Licensed CC0.

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