Researchers reveal that a function of a protein that protects cells from being damaged during injuries could be used to develop a number of treatments for various conditions including cardiovascular disease and Alzheimer’s disease. Researchers report online June 7 in the journal Cell that a type of protein called thrombospondin activates a protective pathway that prevents heart cell damage in mice undergoing simulated extreme hypertension, cardiac pressure overload and heart attack.
"Our results suggest that medically this protein could be targeted as a way to help people with many different disease states where various organs are under stress,'' said Jeffery Molkentin, PhD, lead investigator and a researcher at Cincinnati Children's Hospital Medical Center and the Howard Hughes Medical Institute. "Although more study is needed to determine how our findings might be applied clinically, a possible therapeutic strategy could include a drug or gene therapy that induces overexpression of the protein in tissues or organs undergoing injury."
Thrombospondin (Thbs) proteins are produced by the body in cells where tissues are being injured, reconfigured or remodeled, such as in chronic cardiac disease. They appear in part of the cell's internal machinery called the endoplasmic reticulum. There, Thbs triggers a stress response process to regulate production of other proteins and help correct or rid cells of proteins that misfold and lose their form and intended function. Misfolded proteins help drive tissue damage and organ dysfunction.
The researchers zeroed in on how one thrombospondin protein (Thbs4) activates cellular stress responses in mice bred to overexpress the protein in heart cells. They compared how the hearts of the Thbs4-positive mice responded to simulated stress and injury to mice not bred to overexpress cardiac-specific Thbs4.
Overexpression of Thbs4 had no effect on the animals prior to cardiac stress – although during simulated hypertension and cardiac infarction the protein reduced injury and protected them from death. Mice not bred for Thbs4 overexpression were extremely sensitive to cardiac injury, according to Molkentin, a member of the Division of Molecular Cardiovascular Biology and Cincinnati Children's Heart Institute.
The researchers reported that overexpressed Thbs4 enhanced the ability of heart cells to secrete helpful proteins, resolve misfolded proteins and properly reconstruct extracellular matrix – connective tissues that help give the heart functional form and structural integrity.
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Mice bred not to overexpress cardiac Thbs4 did not exhibit activated Aft6alpha or robust repair processes following cardiac injury, leading to their poor outcomes.
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Source-Eurekalert