Researchers at the University of Miami Miller School of Medicine and the Miami Veterans Administration Medical Center have received a four-year, $1.5 million grant to study how the SARS-CoV-2 virus instigates myocarditis, a generally rare form of heart muscle inflammation.
The research group will investigate the virus’s relationship with cardiac low-density lipoprotein (LDL) receptors, which could potentially become a therapeutic target. The LDL receptor is best known for binding LDL cholesterol,” said Lina Shehadeh, Ph.D., professor of cardiovascular medicine and principal investigator on the grant as well as a researcher at the Veterans Administration (VA) Medical Center.
“But we found that, when these receptors are overexpressed, the heart becomes highly susceptible to the viral inflammatory response causing myocarditis. If we understand why some people get myocarditis, we can start thinking about prevention and treatment.”
Translational Team Science
Dr. Shehadeh will lead an interdisciplinary team to investigate how the LDL receptor interacts with SARS-CoV-2:
Sylvia Daunert, Pharm.D., Ph.D., professor and Lucille P. Markey chair of the Department of Biochemistry and Molecular Biology at the Miller School
Sapna Deo, Ph.D., professor of biochemistry and molecular biology and director of molecular medicine pathway of biochemistry and molecular biology at the Miller School
Leonardo Tamariz, M.D., professor of public health sciences and cardiology at the Miller School and a VA researcher
Keith Webster, Ph.D., professor of molecular and cellular pharmacology at the Miller School
Joshua Hare, M.D., Louis Lemberg Professor of Medicine, chief science officer and senior associate dean for experimental and cellular therapeutics as well as a professor of cardiology, biomedical engineering and molecular and cellular pharmocology at the Miller School
Jose Capcha, Ph.D., assistant professor of cardiovascular medicine at the Miller School, who is co-leading the study
“This work is an example of translational team science, where the merging of nanotechnology with basic science will help us understand the important health consequences of SARS infection in the heart,” said Dr. Daunert.
SARS-CoV-2 And LDL Receptors
Using a new animal model of COVID-induced myocarditis, the researchers will dissect the biochemical interactions between SARS-CoV-2 and LDL receptors. From there, they hope to determine whether LDL receptor blockers provide therapeutic benefits.
The group will also be using patient blood samples to study the immune cell signatures in patients with myocarditis. The inflammatory monocytes that drive this condition can be readily quantified to better understand the immune response that is helping drive it.
“When placed in a dish with cardiac cells with more LDL receptors, human monocytes are more overreactive,” said Dr. Shehadeh. “This confirms our hypothesis that, when there are more LDL receptors, there is greater immune over-reactivity.
We believe we can hit this system with drugs that block LDL receptors and hopefully benefit patients with acute or perhaps long COVID.”
One existing LDL receptor inhibitor, triciribine, is showing early potential. The researchers intend to dive into the drug’s biochemistry and potentially reformat it to make it more effective. One promising avenue could be formulating triciribine as a nanoparticle, since smaller molecules could more efficiently target LDL receptors.
“There are a couple of ways we can go after this,” said Dr. Shehadeh. “We can manage the general inflammation and/or more directly target the LDL receptors. Either way, we hope to develop better options and establish strategies to prevent and treat myocarditis during COVID outbreaks.”