How do people rapidly adapt to the reduced oxygen levels at high altitude? New research led by UTHealth could help answer that question. From the left are Kaiqi Sun, Yujin Zhang, Ph.D., Yang Xia, M.D., Ph.D., and Hong Liu.
How do people rapidly adapt to the reduced oxygen levels at high altitude? New research led by UTHealth could help answer that question. From the left are Kaiqi Sun, Yujin Zhang, Ph.D., Yang Xia, M.D., Ph.D., and Hong Liu.

When people travel to mountainous regions where oxygen is in short supply, their red blood cells release more oxygen to their bodies to counteract the oxygen insufficiency. But, how their bodies do this has been a mystery.

Taking advantage of a rare opportunity to study a group of subjects atop Mt. Chacaltaya in Bolivia, an international research team has identified molecular mechanisms involved in red blood cell function, which the investigators believe could lead to treatments for conditions associated with low oxygen or hypoxia. The mountain’s elevation is about 17,800 feet.

Biochemists from McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth) and scientists with the AltitudeOmics Research Team at the Altitude Research Center at the University of Colorado Anschutz Medical Campus, reported on one mechanism in the journal Nature Communications and another in the journal Circulation.

“If humans don’t adapt to the high altitude, stroke, pulmonary edema, heart problems and even death can occur,” said Yang Xia, M.D., Ph.D., the senior author on both papers and a professor of biochemistry and molecular biology.

“Understanding how the body adapts to high altitude could lead to treatments to offset the insufficiency of oxygen,” Xia said. “Red blood cells are the most abundant circulating cells and only cell type responsible for delivering oxygen. Up until now, little has been known about how the function of red blood cells is regulated at high altitudes to adapt to hypoxia.”

Invited to collaborate with Robert Roach, Ph.D., and his team at the Altitude Research Center on a three-week, high-altitude study involving 21 college students as research volunteers, Xia’s team tested the subjects and identified molecules responsible for improving oxygen delivery from red blood cells under hypoxic circumstances.

Two hundred and thirty three metabolites were identified in human red blood cells at sea level and high altitude by state-of-the-art, high throughput unbiased metabolmic screening as part of a collaboration with Angelo D`Alessandro, Ph.D., and Kirk Hansen, Ph.D.,  of the University of Colorado, Denver.

“We looked for novel signals of molecular adaptation to hypoxia and Dr. Xia and her group found in our samples these signals for a strong upregulation of adenosine and sphingosine 1-phosphate (S1P). Our findings were made possible by combining Dr. Xia’s expertise in the laboratory and our success with comprehensive human experiments at high altitude,” said Roach, AltitudeOmics principal investigator.

Extending from the screening in human samples, Xia’s group conducted human translational studies and sophisticated mouse genetic studies to whittle the metabolites down to two biosignaling metabolites – adenosine and S1P. Specifically, Xia’s group tested the levels of these metabolites at sea level and observed a significant increase of adenosine and S1P during the high altitude stay of the volunteers.

In mouse models of hypoxia, Xia’s group demonstrated that increased levels of adenosine and S1P lead to increased oxygen delivery and protection against tissue hypoxia. Further mechanistic studies demonstrated that an enzyme named AMPK is an important intracellular molecule functioning downstream of adenosine to promote oxygen release to counteract tissue hypoxia.

In preclinical studies in mice, Xia’s group showed that the use of the Food and Drug Administration-approved drug metformin to enhance AMPK enzyme activity lessens tissue hypoxia by triggering oxygen delivery to tissues.

“These two papers show that these pathways are activated at high altitude to promote release of oxygen from red blood cells to provide more oxygen to tissues,” said Rodney E. Kellems, Ph.D., professor and chair of biochemistry and molecular biology.

“The discoveries made by Dr. Xia and her research team provide important new insight regarding physiological mechanisms regulating oxygen release from red blood cells and have important implications not only for adaption to high altitude but also for blood storage, blood transfusion, medical conditions resulting in poor circulation such as pulmonary disease, cardiac disease and genetic conditions resulting in hemolytic anemias such as sickle cell disease and thalassemia,” he said.

The team’s findings, according to Charles E. Wade, Ph.D., deputy director of the Center for Translational Injury Research at McGovern Medical School, could aid in the treatment of trauma patients requiring blood transfusions.

“Many trauma patients have tissue hypoxic and need oxygen rich blood. When patients receive stored blood, it can take hours for the transfused red blood cells to readily deliver oxygen to the tissue. This information could potentially be used to rejuvenate the stored red blood cells,” said Wade, the James H. “Red” Duke, Jr. M.D., Distinguished Professor in Surgery at UTHealth.

“The collaboration between the Houston and Denver groups has resulted in the translation of observations from a field study in humans to the laboratory with comprehensive genetic and molecular biology testing of mice and back to humans with clinical trials underway to manipulate the newly discovered pathways for improved oxygen delivery,” said Roach, noting that Mark Gladwin, M.D., chair of medicine at the University of Pittsburgh, played an instrumental role in the collaboration.

“With our combined expertise and effort, we have published two papers providing both human and mouse evidence that elevated adenosine and S1P promote erythrocyte oxygen delivery to protect against tissue hypoxia. Currently, we are translating our mechanistic and preclinical studies to humans to test if enhancing these newly identified erythrocyte pathways is beneficial to improve quick adaption to high altitude,” Xia said.

“This study is highly significant because it provides therapeutic opportunities for targeting our newly identified metabolites and pathways in humans at high altitude. More importantly, this study will also lead to multiple novel targets to treat numerous disease conditions associated with hypoxia including cardiovascular diseases, respiratory diseases, kidney diseases and even cancers,” Xia said.

The Nature Communications paper, titled “Sphingosine 1-phosphate promotes erythrocyte glycolysis and oxygen release for adaptation to high-altitude hypoxia,” received support from National Institutes of Health grants (HL119549, DK083559, HL113574), Department of Defense grants (W81XWH-11-2-0040, W81XWH-10-2-0114) and the National Blood Foundation.

The Nature Communications coauthors included Kaiqi Sun, Yujin Zhang, Ph.D., Anren Song, Ph.D., Hongyu Wu, M.D., Ph.D., Hong Liu, Morayo Adebiyi, Aji Huang, Yuan Edward Yang Wen, Mikhail Bogdanov, Ph.D.,  Kellems, William Dowhan, Ph.D., Alejandro Vila and John O’Brien, Ph.D.,  of McGovern Medical School; Hansen, D’Alessandro,  Roach, Travis Nemkov, Andrew W. Subudhi, Ph.D., Sonja Jameson-Van Houten and Colleen Julian, Ph.D., of the University of Colorado;  Martin Safo, Ph.D., of Virginia Commonwealth University; and Andrew T. Lovering, Ph.D., of the University of Oregon.

The Circulation paper, titled “Beneficial Role of Erythrocyte Adenosine A2B Receptor–Mediated AMP-Activated Protein Kinase Activation in High-Altitude Hypoxia,” was supported by National Institutes of Health grants (HL119549, DK083559 and HL113574), American Heart Association grant (12IRG9150001) and Department of Defense grants (W81XWH-11-2-0040, W81XWH-10-2-0114).

The Circulation paper coauthors included Hong Liu, Yujin Zhang, Ph.D., Hongyu Wu, Ph.D., Anren Song, Ph.D., Kaiqi Sun, Aji HuangYuan Edward Yang Wen, Harry Karmouty-Quintana, Ph.D., Bihong Zhao, M.D., Ph.D., Jessica Li, Ph.D.,  Ning-Yuan Cheng, Ting Ting Weng, Ph.D., Fayong Luo, Ph.D., Kellems, and Michael Blackburn, Ph.D., of McGovern Medical School; Roach, Hansen, D’Alessandro, Holger Eltzschig, M.D., Ph.D., Travis Nemkov, Andrew W. Subudhi, Ph.D., Sonja Jameson-van Houten and Colleen Julian, Ph.D., of the University of Colorado; Gennady G. Yegutkin, Ph.D., of the University of Turku, Turku, Finland; Hong Sun, M.D., Ph.D., of Central South University, Changsha, Hunan, China; and Andrew T. Lovering, Ph.D., of the University of Oregon.

Blackburn, Dowhan, Karmouty-Quintana, Kellems and Xia are on the faculty of The University of Texas Graduate School of Biomedical Sciences at Houston. Blackburn is one of two deans at the Graduate School as well as the William S. Kilroy, Sr. Chair in Pulmonary Disease and John P. McGovern Graduate School of Biomedical Sciences Endowed Distinguished Professor at UTHealth.