# Hemolysis and free heme signaling in pulmonary hypertension

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2021 · $517,755

## Abstract

Pulmonary arterial hypertension (PAH) is a fatal disease with progressive lung vascular remodeling leading to
right heart hypertrophy and failure. There is an extreme disparity between the prevalence of PAH in the general
population (0.001%) and patients with hemolytic anemias (10-80%). Our previously published data indicate
that idiopathic PAH patients, which have never experienced hemolytic conditions, exhibited 5-fold increase in
free hemoglobin (Hb) levels in plasma, and free Hb levels significantly correlated with PAH progression.
Increased hemolysis has also been observed in pre-clinical PAH models and correlated with a disease
progression. While the pathogenic properties of free Hb have been previously reported, these studies were
mainly focused on free Hb and free heme extracellular functions related to redox and nitric oxide scavenging
activities. Therefore, there is a critical gap in understanding the mechanisms of hemolysis-mediated
intracellular signaling in PAH. Indeed, our preliminary data demonstrated that free heme induces activation of
phosphofructokinase (PFK) via p38/MK2 axis in pulmonary artery endothelial cells and smooth muscle cells
resulting in a metabolic switch toward glycolysis.
Another important question is why PAH patients have increased hemolysis? We recently discovered that the
dysfunction of pyruvate dehydrogenase (PDH), a critical enzyme in metabolic homeostasis, impairs
reticulocyte maturation, and responsible for the accumulation of immature reticulocytes that are susceptible to
rupture. PDH insufficiency is known to be directly involved in PAH pathogenesis by compromising normal
mitochondrial function. We propose that PDH inactivation is also responsible for increased hemolysis in PAH
patients that have no hemolytic disorders otherwise.
Based on our preliminary data, we hypothesize that PDH insufficiency increases intravascular hemolysis and
activates free heme-mediated metabolic switch through stimulation of PFK. This metabolic shift occurred on
the background of PDH dysfunction results in reprogramming of pulmonary vascular cells toward highly
proliferative phenotype and promoted pulmonary vascular remodeling. We will delineate the importance of
heme-mediated pathways in PAH in the following aims: 1) To elucidate the role of heme-mediated signaling in
the activation of a glycolytic switch; 2) To determine the role of pyruvate dehydrogenase (PDH) in hemolysis;
and 3) To examine the crosstalk between heme-mediated signaling and PDH deficiency in EC/SMC
reprogramming.
If successful, this proposal will uncover the mechanisms responsible for a strong association between
hemolytic conditions and PAH, provide the potential treatments for attenuating heme-mediated pathways in
PAH with hemolytic and non-hemolytic background. New targets will be tested in the proposed studies and will
advance therapeutic approaches that are needed due to the lack of adequate PAH treatment options.

## Key facts

- **NIH application ID:** 10152669
- **Project number:** 5R01HL151447-02
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Ruslan Rafikov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $517,755
- **Award type:** 5
- **Project period:** 2020-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10152669

## Citation

> US National Institutes of Health, RePORTER application 10152669, Hemolysis and free heme signaling in pulmonary hypertension (5R01HL151447-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10152669. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*