Growth differentiation factor 15 alleviates diastolic dysfunction in mice with experimental diabetic cardiomyopathy
Jordan S. F. Chan, Seyed Amirhossein Tabatabaei Dakhili, Maria Areli Lorenzana‐Carrillo, Keshav Gopal, Serena M. Pulente, Amanda A. Greenwell, Kunyan Yang, Christina T. Saed, Magnus J. Stenlund, Sally R. Ferrari, Indiresh A Mangra-Bala, Tanin Shafaati, Rakesh Bhat, Farah Eaton, Michael Overduin, Sebastian B. Jørgensen, Gregory R. Steinberg, Erin E. Mulvihill, Gopinath Sutendra, John R. Ussher
Abstract
Growth differentiation factor 15 (GDF15) is a peptide with utility in obesity, as it decreases appetite and promotes weight loss. Because obesity increases the risk for type 2 diabetes (T2D) and cardiovascular disease, it is imperative to understand the cardiovascular actions of GDF15, especially since elevated GDF15 levels are an established biomarker for heart failure. As weight loss should be encouraged in the early stages of obesity-related prediabetes/T2D, where diabetic cardiomyopathy is often present, we assessed whether treatment with GDF15 influences its pathology. We observed that GDF15 treatment alleviates diastolic dysfunction in mice with T2D independent of weight loss. This cardioprotection was associated with a reduction in cardiac inflammation, which was likely mediated via indirect actions, as direct treatment of adult mouse cardiomyocytes and differentiated THP-1 human macrophages with GDF15 failed to alleviate lipopolysaccharide-induced inflammation. Therapeutic manipulation of GDF15 action may thus have utility for both obesity and diabetic cardiomyopathy.