A Wayne State University School of Medicine scientist is exploring how removing a stress-related protein inside the body’s insulin-producing cells might be key to preventing a common form of heart failure.
The condition, called Heart Failure with preserved Ejection Fraction, or HFpEF, happens when the heart still pumps well but becomes stiff and doesn’t fill properly. HFpEF accounts for more than half of all heart failure cases, and is especially rampant in older adults and individuals with hypertension, obesity and type 2 diabetes. The condition lacks effective treatment.
Using a mouse model that mimics the condition, Professor of Physiology Nour-Eddine Rhaleb, Ph.D., FAHA, and a team of collaborators discovered that removing a key stress-related protein called C/EBP Homologous Protein, or CHOP, from beta cells in the pancreas helped protect the model from heart and kidney damage, high blood pressure and poor physical endurance, even when they were exposed to conditions known to trigger HFpEF.
“These findings suggest that targeting this protein in beta cells might one day help prevent or treat HFpEF in people,” he said.
The resulting study, “Novel insights into beta cell ER stress CHOP and its role in HFpEF development,” is published in the journal Cardiovascular Diabetology.
Dr. Rhaleb, a senior staff scientist at Henry Ford Health, is the co-principal investigator of the study, along with collaborator and co-principal investigator Khalid Matrougui, Ph.D., a professor of Physiological Sciences at Macon & Joan Brock Virginia Health Sciences at Old Dominion University in Norfolk, Va.
Prolonged endoplasmic reticulum stress in pancreatic beta cells, particularly through the CHOP protein, could play a direct and previously unrecognized role in the development of HFpEF.
“Deleting CHOP in beta cells prevented heart dysfunction, inflammation, vascular problems and metabolic stress in mice exposed to HFpEF-inducing conditions. This is groundbreaking because it shifts part of the focus in HFpEF from the heart itself to pancreatic beta cells, opening new avenues for treatment that target metabolic and inflammatory pathways,” Dr. Rhaleb said.
The research builds upon the team’s broader work investigating cardiometabolic disease mechanisms, particularly how metabolic stress and inflammation contribute to cardiovascular and renal injury and dysfunction.
“We have previously studied hypertension, endothelial dysfunction, inflammation and heart failure models. This project expands that focus into the pancreas-heart axis, reinforcing our long-standing interest in the systemic regulation of cardiovascular disease,” Dr. Rhaleb said.
Moving forward, the team will test CHOP inhibitors or gene therapy targeted to beta cells; identify specific factors released from beta cells that trigger heart inflammation; investigate CHOP’s role in female mice to account for sex differences in HFpEF; and translate findings into clinical trials, particularly in patients with diabetes or prediabetes who are at high risk of HFpEF.
Dr. Rhaleb’s contributions are supported in part by the National Institutes of Health award HL136456.