A group from Johns Hopkins Medicine has found that protein clumping in the heart could contribute to the development of heart failure, similar to how protein clumps accumulate in the brain’s of people suffering from neurodegenerative diseases like Alzheimer’s and Parkinson’s.
The researchers identified that the protein desmin tends to clump, and then visualized the clumps in the diseased heart using a noninvasive positron emission tomography (PET) scan.
“From a molecular standpoint there’s not a unified, clear mechanism for why the heart goes into failure,” Giulio Agnetti, PhD, assistant professor of medicine at the Johns Hopkins University School of Medicine and University of Bologna, said in a statement. “But by figuring out this mechanism, we may be able to devise better treatments and diagnostic tools.”
In 2014, the researchers showed that desmin, which is found in the cells’ supporting structure, accumulates in clumps called amyloid in the hearts of dogs with heart failure.
In the new study, the researchers studied the proteins from heart tissue biopsies from people with or without heart failure by using a fluorescent antibody often used in Alzheimer’s research with a new fluorescent stain for amyloid.
This combination allowed the researchers to visualize and quantify the desmin protein clumps and observe twice as many desmin clumps in heart failure patients than those without heart failure.
The team also used a common mouse model of heart failure to look for desmin clumps, where the aorta is surgically constricted, raising the pressure and stress to cause heart failure.
After four weeks of pressure on the aorta, the mice develop symptoms of heart failure such as an enlarged heart and lung congestion. Desmin amyloid was more than doubled in the heart failure mice when using the same antibody and staining techniques used for the human tissue samples.
The researchers then treated proteins from the mice hearts with epigallocatechin gallate (EGCG)—a chemical in green tea known to break up amyloid. The treatment cut by half the amount of protein clumps.
“Interestingly, green tea has already been demonstrated to curb the incidence of cardiovascular disease as well as improve cognitive impairment in Alzheimer’s models, though the mechanism for such action is unclear,” Agnetti said. “EGCG’s ability to ‘de-clump’ these sticky proteins could be one of green tea’s healthy effects. Knowing how this chemical works could open new avenues for designing a new class of drugs that target protein clumping.”
The researchers then wanted to identify the form of desmin that tended to clump, believing that it was one or more chemical phosphate groups added to the 27th or 31st building blocks in desmin’s protein structure that affects how the protein clumps.
They genetically engineered versions of desmin with one, both or none of the phosphate groups attached to desmin, tagged them with a green fluorescent signal to make them visible, and put them in heart cells using a virus.
After a week, the cells with desmin and two phosphate groups were still pumping, which the researchers said shows that the desmin with two phosphate groups is most likely the normal, healthy version of the protein.
The cells that had a single phosphate on desmin at the 31st position in the protein’s chain of amino acids contracted more rapidly and had more green clumps. The researchers believe this shows that they behave as the diseased version of the protein.
The researchers then tested if they could use a noninvasive technique to detect desmin clumps in mice with heart failure by injecting healthy and heart failure mice with Amyvid, a radioactive dye that enabled the team to see the protein clumps by PET.
The heart failure mice had 13 percent more of the Amyvid taken up in their hearts than the healthy mice.
According to the U.S. Centers for Disease Control and Prevention, about 5.7 million people in the U.S. have heart failure, half of which will likely die within the next five years.
The researchers will next attempt to confirm the results in more human tissue samples and identify a drug or small molecule to prevent desmin from forming clumps.
The study was published in Circulation Research.
