(Editor's Note: The news embargo lifted at noon on March 11, and this research article was posted March 14 on the PNAS website. Here's the link.)
March 11, 2013
The research, in the lab of cardiologist and cell biologist Nipavan Chiamvimonvat of the School of Medicine’s Division of Cardiovascular Medicine, utilized a treatment involving a compound synthesized by Sing Lee and Sung Hee Hwang in the lab of UC Davis entomologist Bruce Hammock.
In research published this week in the Proceedings of National Academic of Sciences, the 11-scientist team from the Chiamvimonvat and Hammock labs determined the molecular mechanisms underlying the beneficial effects of soluble epoxide hydrolase (sEH) inhibitors in a heart attack.
“Our study provides evidence for a possible new therapeutic strategy to reduce cardiac fibrosis and improve cardiac function after a heart attack,” Chiamvimonvat said.
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.
“Cardiac fibrosis or the abnormal thickening of the heart tissues results from an increase in the proliferation of cardiac fibroblasts, cells in the connective tissues that produce collagen and other fibers,” she said. “After a heart attack, the loss of cardiac myocytes can culminate in cardiac fibrosis and abnormal cardiac remodeling leading to eventual heart failure.” Myocytes, or heart muscle cells, are critical in the normal function of the heart as a pump.
López said that tissue fibrosis “represents one of the largest problems in treating heart diseases for which there are few effective therapies currently. In the heart, adverse cardiac remodeling consists of enlargement of heart muscle cells (also termed cardiac myocyte hypertrophy), tissue fibrosis, and electrical perturbations and represents the prevailing response of the heart to abnormal stimuli, for example, after a heart attack or with long standing high blood pressure (hypertension).”
The Hammock/Chiamvimonvat collaborations earlier demonstrated the beneficial effects of several compounds that are potent inhibitors of the soluble epoxide hydrolase in different models of cardiac enlargement and heart failure. In this study, they treated murine (rodent) patients with the compound that resulted in “significant improvement in cardiac function after a heart attack.”
“There is significant decrease in cardiac myocyte hypertrophy associated with a decrease in the expression of fetal gene program,” they wrote in the abstract. Treatment also resulted in a significant decrease in cardiac fibrosis and a reduction in the migration of fibroblasts into the heart from bone marrow.” Fibroblasts are cells in the connective tissues that produce collagen and other fibers.
“Treatment with the inhibitor not only prevents the development of pathologic cardiac myocyte hypertrophy, the compound may also result in an improvement in diastolic dysfunction by decreasing cardiac fibroblast proliferation and cardiac fibrosis,” said López. Diastolic dysfunction, a future direction of the research but not covered in the research paper, refers to the abnormal relaxation of the heart after each beat, a condition commonly seen with excessive cardiac fibrosis while cardiac myocyte hypertrophy refers to the enlargement of the heart muscle cells.
“This study is the result of a long-term and exciting collaboration between the College of Agricultural and Environmental Sciences and the UC Davis School of Medicine which has been very productive,” said Hammock, a distinguished professor of entomology who has a joint appointment with the UC Davis Comprehensive Cancer Research Center. He has collaborated with Chiamvimonvat since 2005. “Not only did we do things we could never have done on our own but the interaction with Dr. Chiamvimonvat, Dr. Lopez and their team has made the project both educational and fun. Moreover, I think the translational value of the study could really be very significant."
The project drew major support from the National Institutes of Health, Veterans’ Administration, the Howard Hughes Medical Institute Med-into-Grad Training Program to UC Davis, American Heart Association, Western States Affiliate Predoctoral Fellowship Award, Fellow-to-Faculty Award from Sarnoff Cardiovascular Research Foundation, and the Harold Amos Medical Faculty Development Award from Robert Wood Johnson Foundation.
Partial support came from a National Institute of Environmental Health (NIEHS) grant, the NIEHS Superfund Basic Research Program, the NIEHS Center for Children’s Environmental Health and Disease Prevention, a Technology Translational Grant from UC Davis Health System, and from the American Asthma Society. Hammock is a George and Judy Marcus Senior Fellow of the American Asthma Society.
Chiamvimonvat and Hammock have filed patents with the University of California for sEH inhibitors and cardiac hypertrophy therapy and organ fibrosis. “We have been working for the last 17 months with UC Davis to get options to the technologies from our laboratories and move them toward the clinic,” Hammock said. “I think we are close to an agreement with UC Davis to do this, but it is daunting to think of raising the funding for this effort in this economic climate.”
--Kathy Keatley Garvey
Communications specialist
UC Davis Department of Entomology
(530) 754-6894