Proteotoxic stress over time can cause irreversible cardiac abnormalities. Proteotoxicity, the damage caused by faulty proteins, contributes to a severe form of heart disease.
Rajasekaran Namakkal-Soorappan, Ph.D., an associate professor in the Division of Molecular and Cellular Pathology, is leading a team of researchers who have identified a group of microRNAs, ProteotoxomiRs, that play a crucial role in proteotoxic cardiac disease in mouse models. The study “ProteotoxomiRs: Diagnostic and Pathologic miRNA Signatures for Reductive Stress Induced Proteotoxic Heart Disease” was published in Redox Biology.
ProteotoxomiRs regulate how heart cells respond to the accumulation of damaged proteins, which impairs cardiac function. Their dynamic changes throughout disease progression could make them valuable biomarkers for early detection.
Researchers noticed that certain microRNAs acted protectively in early disease by stabilizing proteins. As disease advanced, other microRNAs became overactive and contributed to cardiac dysfunction. This shift in function could assist in distinguishing between early and advanced disease stages.
“The mutant R120G-aB crystallin protein drives this process by inducing reductive stress, leading to toxic protein aggregates in heart cells,” Namakkal-Soorappan said. “In our study, early-stage aggregates appeared at six weeks and progressed to severe heart dysfunction by six months. This accumulation of protein toxicity disrupts normal heart function and contributes to heart failure.”
Sooryanarayana Varambally, Ph.D., MBA., a key collaborator in this study and professor in the Division of Molecular and Cellular Pathology,
believes ProteotoxomiRs could serve as non-invasive biomarkers for early heart disease screening in blood tests.
“These targets must be tested for their ability to control or minimize proteotoxic development, potentially preventing or delaying the onset of heart failure,” said Varambally.
Santhosh Kumar Karthikeyan, Ph.D., first author and researcher, highlighted that some ProteotoxomiR targets may benefit from existing cancer drugs as prophylactic or therapeutic agents against proteotoxic insults.
Collaborators with Namakkal-Soorappan, Varambally and Karthikeyan include, Jarrell Matthew Cleveland, Ahila Arulmani, Ashvanthi Raveendran, Mariam Karimi, Mohammed Owais Ansari and Anil Kumar Challa from the UAB Department of Pathology, Palanisamy Nallasamy and Moorthy P. Ponnusamy from the University of Nebraska Medical Center, and Ivor J. Benjamin from the Medical College of Wisconsin, Milwaukee.
“The next step is to validate these findings in human heart tissues to confirm that ProteotoxomiRs are similarly expressed in cardiac patients,” said Namakkal-Soorappan. “If successful, this could lead to precision medicine strategies in heart disease. Identifying proteotoxicity early and targeting the right pathways could prevent irreversible damage and improve outcomes.”