# HIF-Mediated Detrimental Consequences of Chronic Intermittent Hypoxia

> **NIH VA I01** · VA SALT LAKE CITY HEALTHCARE SYSTEM · 2020 · —

## Abstract

Obstructive sleep apnea (OSA), a term for periods during sleep when breathing is blocked or impeded,
is a highly prevalent medical condition, increases with obesity and diabetes, and affects 9-18% of the adult
U.S. population. OSA occurs because of recurrent upper airway collapse during sleep leading to reductions in
airflow with cyclic changes in body oxygen, and results in a state of chronic intermittent hypoxia. Many
essential processes, such as production of red blood cells, energy regulation, and formation of new blood
vessels, are regulated by hypoxia. OSA is an exceedingly common problem that has been linked to high blood
pressure, diabetes, poor memory and heart attacks. Hypoxia leads to up-regulation of hypoxia-inducible factors
(HIFs). HIF-1 and HIF-2 were discovered as a result of studies of erythropoietin (EPO), the key hormone that
stimulates erythroid progenitors and regulates the production of erythrocytes, the subject of the PI's previous
VA support.
 This application is designed to gain novel insights into the contribution of HIFs, which regulate
erythropoiesis, to the pathophysiology of OSA. The PI of this proposal has been intrigued that, in contrast to
other hypoxic conditions, his major clinical/academic focus of polycythemia/erythrocytosis is not a common
feature of OSA. During prolonged hypoxia, HIFs mediate an increase in erythropoiesis, leading to an increased
red blood cell (RBC) mass. Upon return to normoxia, the increased RBC mass is abruptly overcorrected by
the preferential destruction, i.e., hemolysis, of hypoxia-formed young RBCs, a phenomenon termed
neocytolysis. We created a novel mouse model of neocytolysis and used this model to show that neocytolysis
is mediated by excessive accumulation of reactive oxygen species (ROS), increased mitochondria in RBCs,
and increased micro RNA miR-21 which down-regulates catalase.
 We also obtained preliminary data suggesting that neocytolysis is the main mechanism preventing
polycythemia in patients with OSA. We observed that erythrocytes and reticulocytes of OSA patients have
reduced catalase transcripts and activity, along with increased miR-21, and that these levels normalize with
CPAP treatment. We also observed that in uncorrected OSA, increased mitochondrial mass and levels of ROS
are found not only in reticulocytes and mature RBCs, but also in other blood cells such as platelets, T-cells, B-
cells, granulocytes, and mononuclear cells. With CPAP treatment, mitochondrial ROS decrease and
mitochondrial mass normalizes.
 To accomplish our research goals outlined in this research proposal, we will elucidate OSA changes in
HIF-regulated pathways using peripheral blood cells to confirm our preliminary findings that neocytolysis
occurs secondary to chronic intermittent hypoxia in most OSA patients. We will determine the metabolic
consequences of chronic intermittent versus sustained hypoxia in a mouse model of neocytolysis and assess
the effect(s) of pharmacological manipulatio...

## Key facts

- **NIH application ID:** 9856937
- **Project number:** 5I01CX001372-04
- **Recipient organization:** VA SALT LAKE CITY HEALTHCARE SYSTEM
- **Principal Investigator:** JOSEF T PRCHAL
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9856937

## Citation

> US National Institutes of Health, RePORTER application 9856937, HIF-Mediated Detrimental Consequences of Chronic Intermittent Hypoxia (5I01CX001372-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9856937. Licensed CC0.

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