| Autor: |
Papadaki M; Loyola University Chicago, Department of Cell and Molecular Physiology, Chicago, Illinois, USA., Holewinski RJ; Cedars-Sinai Medical Center, Heart Institute, Los Angeles, California, USA., Previs SB; University of Vermont, Department of Molecular Physiology and Biophysics, Burlington, Vermont, USA., Martin TG; Loyola University Chicago, Department of Cell and Molecular Physiology, Chicago, Illinois, USA., Stachowski MJ; Loyola University Chicago, Department of Cell and Molecular Physiology, Chicago, Illinois, USA., Li A; University of Vermont, Department of Molecular Physiology and Biophysics, Burlington, Vermont, USA., Blair CA; University of Kentucky, Department of Physiology, Lexington, Kentucky, USA., Moravec CS; The Cleveland Clinic, Department of Molecular Cardiology, Cleveland, Ohio, USA., Van Eyk JE; Cedars-Sinai Medical Center, Heart Institute, Los Angeles, California, USA., Campbell KS; University of Kentucky, Department of Physiology, Lexington, Kentucky, USA., Warshaw DM; University of Vermont, Department of Molecular Physiology and Biophysics, Burlington, Vermont, USA., Kirk JA; Loyola University Chicago, Department of Cell and Molecular Physiology, Chicago, Illinois, USA. |
| Abstrakt: |
Patients with diabetes are at significantly higher risk of developing heart failure. Increases in advanced glycation end products are a proposed pathophysiological link, but their impact and mechanism remain incompletely understood. Methylglyoxal (MG) is a glycolysis byproduct, elevated in diabetes, and modifies arginine and lysine residues. We show that left ventricular myofilament from patients with diabetes and heart failure (dbHF) exhibited increased MG modifications compared with nonfailing controls (NF) or heart failure patients without diabetes. In skinned NF human and mouse cardiomyocytes, acute MG treatment depressed both calcium sensitivity and maximal calcium-activated force in a dose-dependent manner. Importantly, dbHF myocytes were resistant to myofilament functional changes from MG treatment, indicating that myofilaments from dbHF patients already had depressed function arising from MG modifications. In human dbHF and MG-treated mice, mass spectrometry identified increased MG modifications on actin and myosin. Cosedimentation and in vitro motility assays indicate that MG modifications on actin and myosin independently depress calcium sensitivity, and mechanistically, the functional consequence requires actin/myosin interaction with thin-filament regulatory proteins. MG modification of the myofilament may represent a critical mechanism by which diabetes induces heart failure, as well as a therapeutic target to avoid the development of or ameliorate heart failure in these patients. |
