Take entomologist Bruce Hammock, distinguished professor of entomology at the University of California, Davis. Forty years ago, while studying insect development, he discovered a group of anti-inflammatory compounds called sEH (soluble epoxide hydrolases) inhibitors.
In 2005 he began collaborating with cardiologist and cell biologist Nipavan Chiamvimonvat of the School of Medicine’s Division of Cardiovascular Medicine.
Fast forward to today.
Today an 11-scientist team from the Chiamvimonvat and Hammock labs published groundbreaking research in the Proceedings of National Academic of Sciences that shows a new treatment may help prevent and reduce cardiac fibrosis, a common occurrence in patients after a heart attack.
The research utilized a treatment involving a compound synthesized by Sing Lee and Sung Hee Hwang in the Hammock lab. The scientists determined the molecular mechanisms underlying the beneficial effects of soluble epoxide hydrolase (sEH) inhibitors in a heart attack.
“Our study (using rodents) provides evidence for a possible new therapeutic strategy to reduce cardiac fibrosis and improve cardiac function after a heart attack,” Chiamvimonvat told us.
Every year some 935,000 U.S. residents have a heart attack, according to the Centers for Disease Control and Prevention. Heart disease kills about 600,000 a year, accounting for one in every four deaths in the nation.
The research, “New Mechanistic Insights into the Beneficial Effects of Soluble Epoxide Hydrolase Inhibitors in the Prevention of Cardiac Fibrosis,” is “really important in terms of understanding a unique pathway which may be targeted to reduce fibrosis and adverse cardiac remodeling,” Chiamvimonvat said.
The lead authors of the research paper are Padmini Sirish and Ning Li of the Chiamvimonvat lab, and Jun-Yan Liu of the Hammock lab. In addition, other researchers involved in the project are Kin Sing Stephen Lee, and Sung Hee Hwang of the Hammock lab; Hong Qiu, Cuifen Zhao, and Siu Mei Ma of the Chiamvimonvat lab, and López, who developed the methods to quantitate the fibrotic cells using flow cytometry.
Chiamvimonvat and Hammock have filed patents with the University of California for sEH inhibitors and cardiac hypertrophy therapy and organ fibrosis.
A multi-talented scientist and administrator, Hammock holds a joint appointment with the UC Davis Comprehensive Cancer Research Center, and directs the campuswide Superfund Research Program, National Institutes of Health Biotechnology Training Program, and the National Institute of Environmental Health Sciences (NIEHS) Combined Analytical Laboratory. He is a fellow of the Entomological Society of America, a member of the prestigious National Academy of Sciences, and the recipient of the 2001 UC Davis Faculty Research Lecture Award and the 2008 Distinguished Teaching Award for Graduate and Professional Teaching.
Pest management. Pain management.
Early in his career, entomologist Bruce Hammock, now a distinguished professor of entomology at the University of California, Davis and a newly selected fellow of the Entomological Society of America, probed regulating the development of insect larvae.
Now his interests swing toward pain management, including inflammatory diseases like arthritis.
His is truly a case of "from the bench to the bedside."
Today two UC Davis labs--including Hammock's--and a lab from Peking University, China published an article in Proceedings of the National Academy of Sciences (PNAS) that is sure to offer hope down the road for those suffering from arthritis pain.
The scientists found a novel mechanism as to why the long-term, high-dosage use of the well-known arthritis pain medication, Vioxx, led to heart attacks and strokes. Their groundbreaking research, done with rodents, may pave the way for a safer drug for millions of arthritis patients who suffer acute and chronic pain.
“This is a major breakthrough that can lead to a better medication for people suffering from acute pain,” said Hammock, who has a joint appointment at the UC Davis Cancer Center.
The Hammock lab and two others labs--the lab of cell biologist Nipavan Chiamvimonvat, UC Davis Division of Cardiovascular Medicine, and physiologist Yi Zhu, Peking University--used metabolomic profiling to analyze murine (rodent) plasma. They discovered that Vioxx causes a dramatic increase in a regulatory lipid that could be a major contributor to the heart attacks and strokes associated with high levels of the drug and other selective COX-2 inhibitors, known as “coxibs.”
“Our metabolomics study discovered that 20-hydroxyeicosatetrasanoic acid, also known as 20-HETE, contributes to the Vioxx-mediated cardiovascular events,” said UC Davis bioanalytical chemist Jun-Yan Liu, the senior author of the paper and a five-year member of the Bruce Hammock laboratory.
Millions of arthritis patients took Vioxx before its withdrawal from the global market in 2004. Vioxx, a nonsteroidal anti-inflammatory drug (NSAID) and coxib for acute and chronic pain, particularly for arthritis and osteoarthritis, was on the market for five years. Merck & Co. voluntarily withdrew it in September 2004 due to concerns about the increased risk of heart attacks and strokes.
The chronic administration of high levels of selective COX-2 inhibitors, particularly rofecoxib, and valdecoxib, increases the risk for cardiovascular disease, Liu said.
Urologist Ralph devere White, professor of urology at the UC Davis School of Medicine and director of the UC Davis Cancer Center, described the research as “extremely exciting.”
“Vioxx and other drugs in this class were looked on as extremely promising in moderation,” devere White said. “The fact that the Hammock lab discovered why the drug could lead to heart attacks and strokes and is able to quantify the deleterious facts is extremely exciting. I hope that patients can safely use this drug in the future or block the deleterious effects so it will have all of the benefits and none of the adverse side effects.”
Nationally, some 46 million individuals suffer from arthritis. “And almost one million patients are admitted to hospitals every year because of their arthritis,” Hammock said. “They do need effective and safer drugs to relieve their pain.”
This research (see the UC Davis Department of Entomology website) will undoubtedly open up new strategies to develop safer coxibs.
Call it serendipity. Call it a major collaborative effort. Call it a keen eye for science.
Whatever you call it, research that sprang from studies on insect pest control in the Bruce Hammock lab at the
We all know of people suffering from heart failure, which occurs when the heart can’t pump enough blood throughout the body. The condition affects 5 million people in the
The research in the laboratories of cardiologist and cell biologist Nipavan Chiamvimonvat, Department of Cardiovascular Medicine, UC Davis School of Medicine, and entomologist Bruce Hammock, Department of Entomology, showed that the new class of drugs reduces heart swelling in rat models with heart failure.
“This holds promise to treat heart failure and other cardiovascular as well as kidney problems,” said nephrology professor Robert Weiss, Department of Internal Medicine.
Similar compounds are now in clinical trials.
"The study of rat models showed that heart failure is driven by high angiotensin associated with high blood pressure, artery disease and some kidney disease,” Hammock said. “When that occurs, a key enzyme called soluble epoxide hydrolase is increased."
The 11-member research team showed they could inhibit the enzyme with a drug made by Paul Jones, a former postgraduate researcher at UC Davis. The swelling and ultimate failure of the heart is blocked and reversed, Hammock said.
“Interestingly, the increase in heart size associated with extreme exercise does not increase levels of the epoxide hydrolase, and exercise induced heart enlargement fortunately is not blocked by the drug.”
This research follows earlier studies reported from the Chiamvimonvat laboratory on cardiac hypertrophy. The two UC Davis laboratories collaborated with the laboratories of John Shyy at UC Riverside and Yi Zhu, Cardiovascular Sciences,
The paper, “Soluble Epoxide Hydrolase Plays an Essential Role in Angiotensin II-Induced Cardiac Hypertrophy,” is online.
This is definitely a significant discovery that could result in saving scores of lives. And to think it all started with the Hammock lab discovering an enzyme inhibitor that regulates insect larvae development.