New study explores cell receptor crucial for cardiovascular health

August 3, 2022

Cardiovascular diseases remain a leading cause of death around the world. A primary contributor to these afflictions is high blood pressure, or hypertension.

While treatments exist for the condition, which affects tens of millions of Americans, these remedies are not without side effects, and some variants of the disorder are treatment-resistant. The need for more effective therapies to address hypertension-related disease is therefore acute. Illustration showing a portion of the receptor pGC-A known as the extracellular domain, which protrudes from cell surfaces in the cardiovascular system. The illustration shows a portion of the receptor pGC-A, known as the extracellular domain, which protrudes from cell surfaces in the cardiovascular system. Small molecules bind with the receptor and exert subtle control over blood pressure. The new research offers the first sneak peek at the full-length receptor, a vital step in the development of new drugs to treat hypertension and other afflictions. Graphic by Jason Drees Download Full Image

To accomplish this however, biologists need more detailed maps of the mechanisms underlying cardiovascular regulation. One such regulator is a protein receptor that sits atop cardiovascular cells, acting as a conduit for messages that are transmitted when specific hormone molecules bind with them.

Known as pGC-A, this membrane receptor acts a bit like a thermostat, sensitively adjusting the body’s blood pressure to maintain a homeostatic balance essential for health. The receptor acts not only as a vital cellular component for vascular and cardiac homeostasis, but also plays an important role in lipid metabolism and is implicated in cancer development.

In a new study, published in the current issue of the journal Scientific Reports, researchers from Arizona State University's Biodesign Center for Applied Structural Discovery and their colleagues, in collaboration with Mayo Clinic, Rochester, make critical progress toward unveiling the structure of pGC-A.

The study provides the first purification, characterization and preliminary structural analysis of the full-length protein receptor. The research advances include crystallizing the protein and showing that these crystals diffract X-rays — two critical steps essential to solving the structure.

A clearer understanding of this complex receptor and its signaling mechanisms paves the way for a new suite of anti-hypertensive drugs, which could help stave off heart attacks and strokes and improve recovery from these incidents.

Debbie Hansen

"This accomplishment is the first described X-ray diffraction for a new class of membrane protein receptors, and represents an extraordinary effort by our graduate student, Shangji Zhang,” says co-author and Biodesign researcher Debbie Hansen. “Structures of unique classes of membrane proteins often require years of effort and are built on similar critical advances."

Co-author John C. Burnett Jr., from the Department of Cardiovascular Medicine, Mayo Clinic, Rochester, has been working to develop candidate molecules for new anti-hypertensive drugs, based on the structure of the pGC-A receptor.

Heart-stopping threat

According to the World Health Organization, over a third of all deaths worldwide may be attributed to cardiovascular disease. Hypertension is among the leading factors contributing to the progression of cardiovascular disease.

The burden of hypertension has been steadily growing, resulting in a recent recommendation by the Report of the National Heart, Lung and Blood Institute Working Group on Hypertension to “develop new drugs and treatments to target diverse hypertensive patient populations, such as patients with resistant hypertension.”

Treatment-resistant forms of hypertension, which are more likely to occur in patients with obesity, diabetes or renal dysfunction, account for 12–15% of hypertensive patients. Such individuals show limited or poor response to existing therapeutics. The condition can develop when the blood vessels become calcified and inelastic, losing their ability to fully contract and relax. Clinical studies show that treating high blood pressure reduces the risk of stroke by 35–40%, and the risk of heart failure by 50%.

Cardiovascular diseases include rheumatic and congenital heart disease; coronary, cerebral and peripheral arterial disease; deep vein thrombosis; and pulmonary embolism. Coronary artery disease, a leading killer, occurs when blood flow to heart muscle cells is reduced or obstructed, which can lead to heart failure. In the United States alone, the condition is projected to increase to $70 billion by the year 2030.

New insights begin to crystalize

The pGC-A membrane receptor exists in three primary forms. This class of receptors are so important, they comprise the majority of pharmaceutical drug targets. For most organisms, whether prokaryotes like bacteria or eukaryotes like mammals, a full 20–30% of the genome is devoted to the expression of membrane proteins. Such receptors protrude from the outer cell membrane and penetrate deep into the cell’s interior, often acting as conduits for external signals that modify the cell’s behavior.

Designing drugs to target membrane proteins however, requires a highly detailed blueprint of the receptor structure, usually with atomic-scale resolution. Using this information, drug designers can engineer a drug that will bind in a selective and precise manner with the cell receptor, to produce a given outcome.

In the case of pGC-A, the binding molecules are peptide hormones produced by cells of the cardiovascular system. Known as natriuretic peptide hormones, they occur in natural variations and can also be synthetically designed, using genetic mutation. Part of the receptor’s activity involves the conversion of GTP to cGMP, a molecule essential for the normal function of vital organs.

“The heart is not only a pump but an endocrine gland which produces a highly beneficial hormone called atrial natriuretic peptide (ANP),” Burnett says. “This hormone plays an important role in blood pressure, kidney and over all metabolic balance.” 

Digging deeper

To date, only the extracellular component of the pGC-A receptor has been characterized. The current work is a major step toward characterizing the full-length structure, particularly the transmembrane domain and functional intracellular domain regions, about which little is currently known.

To achieve this, the researchers use a method known as baculovirus protein expression. The process involves turning insect cells into tiny protein production factories. Insect cells resemble human cells in terms of their protein-processing machinery yet are easier and cheaper to grow than mammalian cells. Baculoviral vectors allow researchers to turn an insect virus into a vehicle for delivering the genetic recipe for a protein.

The process involves inserting a gene for making the receptor into a special type of DNA vector or carrier known as a bacmid. The recombinant bacmid carrying the receptor gene is then used to infect insect cells, which begin manufacturing recombinant baculoviruses.

The pGC-A receptor protein can then be extracted, purified and subjected to X-ray crystallography, to determine its structure. The process is tricky, labor-intensive and prone to failure for a variety of reasons. Only a small number of the many existing membrane proteins have been fully characterized, making the preliminary characterization of pGC-A an impressive achievement.

The insect cell expression system offers several advantages for protein expression, particularly in the case of membrane proteins like pGC-A. The technique makes it easier for researchers to extract properly folded membrane proteins directly from the cell membrane, compared with the bacterial expression of misfolded and non-functional proteins common with traditional expression in Escherichia coli (E. coli) bacteria.

Horizon line

Shangji Zhang

First author Zhang, who graduated with a doctorate in biochemistry from ASU in 2021 and is a scientist at 21st Century Bio in Davis, California, carried out the purification of the full-length protein.

“This was a massive accomplishment," Hansen says. "Membrane proteins are not trivial to purify, and she was also able to get crystallization of the protein and X-ray diffraction.”

Further purification and better diffraction data will ultimately enable atomic-level structural characterization. 

The research opens the door to the detailed characterization of other membrane proteins, which may ultimately find their way into effective drugs to control hypertension and a broad range of other medical conditions.

“A major goal is to develop breakthrough drugs based on ANP and its target receptor in humans to treat high blood pressure, heart failure as well as obesity,” Burnett says. “The work done by the ASU and Mayo teams and reported in Scientific Reports helps unlock the secret of the receptor target and will accelerate the development of new drugs and truly help patients worldwide.”

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Petra Fromme

Petra Fromme, director of the Center for Applied Structural Discovery, who is the senior author of this study and served as the PhD supervisor of Zhang, is excited about the high impact of this work.

“Metabolic diseases are one of the most important health threats of the 21st century, with diabetes, high blood pressure and heart diseases taking the lives of millions each year — and the numbers are rising. The work on the pGC-A receptor has the potential to develop an effective drug that reduces the symptoms without serious side effects,” she said.

This project was supported by an award to J.C.B. and P.F. from the Mayo/ASU Structural Biology Alliance and by the Biodesign Center for Applied Structural Discovery at Arizona State University. This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science user facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357.

The research was carried out with the generous assistance of the Biodesign Center for Innovations in Medicine and the Center for Personalized Diagnostics

Richard Harth

Science writer, Biodesign Institute at ASU


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$1M gift to support underserved, emerging writers at ASU

August 3, 2022

A family with longtime philanthropic ties to Arizona State University has made a $1 million gift to the university’s Department of English.

The Swarthout family, whose first gift to ASU was in 1962, has created a new endowment to fund Summer Artistic Development Grants in English’s creative writing program. The grants initiate a series of three programs:

The Glendon F. Swarthout Fellows will be six ASU undergraduates from underserved and underrepresented communities about to enter their final year of study at ASU. They will receive financial and mentoring support to apply to Master of Fine Arts in creative writing programs, including the payment of all test and admission fees, to ensure that their voices find a national stage.

The Kathryn Blair Swarthout Fellows will be four graduating Master of Fine Arts students from ASU’s creative writing program who will be supported as they transition into their careers. Funds will cover expenses like professional development, contest and submission entry fees, manuscript review, research trips and workshops — all with the goal of enabling swift publication of their work. This fund will ensure that we launch our accomplished and diverse writers to early success.

The Swarthout Mentorship Fellows are current Master of Fine Arts in creative writing students who will support the undergraduate fellows for six weeks over the summer through one-on-one meetings as well as group activities.

Jeffrey Cohen, dean of humanities in The College of Liberal Arts and Sciences, of which the Department of English is an academic unit, celebrated the family’s well-timed beneficence and commitment to ASU’s core values.

“This generous gift from the Swarthout family will enable a creative writing program — one of the most noted in the nation — to move to its next level while fully embracing the ASU mission of access and inclusive excellence,” he said. “The Swarthout Summer Artistic Development Grants are a game changer — and our students will benefit immensely.”

Professor of English Sally Ball, who shepherded this most recent gift as director of creative writing, said she was especially gratified about the impact on students.

“Creative writing at ASU is so lucky — especially due to the vision and commitment of Glendon and Kathryn Swarthout’s niece, Blair Vaughn-Gruler and her son Oliver Polzin — to inaugurate this additional Swarthout legacy here at ASU: one that fosters connections between the cohorts, as the graduate fellows mentor the up-and-comers, something we’re especially thrilled about,” she said.

A watershed opportunity

ASU creative writing is highly ranked among the nation’s MFA programs. Its faculty, alumni and students hold positions of leadership in the literary community and are regularly recognized with national and international honors.

Two recent Pulitzer Prize-winners include poet Natalie Diaz who further holds the Maxine and Jonathan Marshall Chair in Modern and Contemporary Poetry — a laudatory post that provides additional ASU support for a “major poet and rising star in the field of American poetry” — and novelist and essayist Mitchell Jackson, the John O. Whiteman Dean’s Distinguished Professor who is also a regular columnist for Esquire and convener of the ASU Conversations in Craft and Content series.

Man teaching a creative writing class

Professor Mitchell Jackson leads a fiction workshop during fall 2021. The ASU creative writing program prides itself on its small class sizes and close mentorship by award-winning faculty. Photo by Jenny Dupuis/ASU Academic Enterprise Communications

In addition to Diaz and Jackson, other notable and award-winning faculty in the program include fiction and nonfiction writers Matt BellJenny IrishTara Ison (currently serving as interim director of the program), T. M. McNally (McNally himself won a Swarthout Award in the 1980s during his student years) and Sarah Viren; and poets Sally BallEunsong KimAlberto RíosSolmaz Sharif and Safiya Sinclair.

A short list of alumni successes includes 2019 graduate Kalani Pickhart, who last month won the New York Public Library’s 2022 Young Lions Fiction Award for her Ukraine-set novel, “I Will Die in a Foreign Land.” The book began as Pickhart’s MFA thesis project.

Fiction writer, ASU journalism alum and current Stanford Professor Adam Johnson pointed to the support he received via the Swarthout Awards – which are open to all students at ASU, not just English majors — as fundamental to his concept of himself as a writer.

“It was my first validation that ‘this thing could happen,’” Johnson told a crowd at the ASU Desert Nights, Rising Stars Writers Conference in 2012. Johnson went on to win the Pulitzer Prize in 2013 for his novel, “The Orphan Master’s Son.” Other Swarthout Award recipients have gone on to receive fellowships from the Bread Loaf Writers Conference, Kundiman and the U.S. Fulbright Commission; and to receive awards including the Cave Canem Poetry Prize, the PEN Southwest Book Award, the Plimpton Prize, the University of Iowa Press John Simmons Award and many others; and their books have been named to "best books of the year" lists from Entertainment Weekly, NPR, the New York Times, the Wall Street Journal and more.

The Swarthout family believes the support helps create a “watershed opportunity” for emerging writers to be taken seriously. The annual awards have often functioned as a kind of springboard to students’ writing careers, providing resources — and confidence, as in Johnson’s case. The goal of the new endowment is similar: to provide a boost for talented writers as they find their footing in their writing and professional lives.

A family legacy

Writers Glendon and Kathryn Swarthout pose in their study in Scottsdale, AZ in this undated photo which is courtesy of the Swarthout Family.

Glendon and Kathryn pose in the study of their Scottsdale, Arizona, home in this undated photo, which is courtesy of the Swarthout family.

Multigenerational giving defines the Swarthout family’s ASU commitment. The inaugural gift in the 1960s was made by writers Glendon and Kathryn Swarthout as a way to help young writers who are struggling financially — in the same way that Glendon was helped by an award early in his career.

Blair Vaughn-Gruler, Glendon and Kathryn Swarthout’s niece and the trustee of the Swarthout Family Trust, said she was pleased to continue this philanthropic legacy at ASU.

“The Swarthout Family Trust is honored to continue supporting ASU creative writers with a new level of financial assistance and mentorship through the Swarthout Summer Artistic Development Grants," she said.

“With the assistance of the ASU Foundation and the excellent work of ASU’s director of creative writing Sally Ball, Glendon and Kathryn Swarthout’s legacy continues to grow and evolve, offering a new layer of critical support to emerging student writers.”

Glendon Swarthout, who died in 1992, taught at ASU from 1959 to 1963. He authored 16 novels, two of which were Pulitzer Prize nominees. Nine others were made into films, including “Bless the Beasts and Children,” “The Shootist,” “Where the Boys Are” and “The Homesman.” 

Kathryn Swarthout, ever the champion of her husband’s work, was a literary force in her own right. She was a columnist for Woman's Day magazine for 26 years and received a Certificate of Merit in Literature from the National Society of Arts and Letters. Together Kathryn and Glendon co-wrote six novellas for young adults, and their papers are held in ASU Library’s Rare Books and Manuscripts. Kathryn died in 2015.

The couple had a son, Miles, also a writer. His adaptation of his father’s novel “The Shootist,” which would become John Wayne’s last film, was nominated for a Writers Guild award. In addition to his work as a journalist and columnist, Miles Swarthout rekindled interest in the novels his parents co-wrote by publishing them as e-books. After his parents’ deaths, he remained actively involved in the Swarthout Awards at ASU — committed to continuing his family’s involvement into another generation — until his own passing in 2016. 

This spring’s awards marked the 60th year of the contest, and they remain among the five most generous prizes in higher education. With this newest endowment, the Swarthout family is poised to make good on Glendon and Kathryn’s oft-praised “determination to make a difference.”

Top photo: Glendon Swarthout’s writing desk resides in the Piper Writers House, home of the Virginia G. Piper Center for Creative Writing at ASU. A framed poster advertising John Wayne’s last film, “The Shootist,” which was based on Swarthout’s novel, leans on the desk. Photo by Kristen LaRue-Sandler/ASU