title: cAMP-dependent Protein Kinase (PKA) Signaling Is Impaired in the Diabetic Heart.
abstract: Diabetes mellitus causes cardiac dysfunction and heart failure that is associated with metabolic abnormalities and autonomic impairment. Autonomic control of ventricular function occurs through regulation of cAMP-dependent protein kinase (PKA). The diabetic heart has suppressed β-adrenergic responsiveness, partly attributable to receptor changes, yet little is known about how PKA signaling is directly affected. Control and streptozotocin-induced diabetic mice were therefore administered 8-bromo-cAMP (8Br-cAMP) acutely to activate PKA in a receptor-independent manner, and cardiac hemodynamic function and PKA signaling were evaluated. In response to 8Br-cAMP treatment, diabetic mice had impaired inotropic and lusitropic responses, thus demonstrating postreceptor defects. This impaired signaling was mediated by reduced PKA activity and PKA catalytic subunit content in the cytoplasm and myofilaments. Compartment-specific loss of PKA was reflected by reduced phosphorylation of discrete substrates. In response to 8Br-cAMP treatment, the glycolytic activator PFK-2 was robustly phosphorylated in control animals but not diabetics. Control adult cardiomyocytes cultured in lipid-supplemented media developed similar changes in PKA signaling, suggesting that lipotoxicity is a contributor to diabetes-induced β-adrenergic signaling dysfunction. This work demonstrates that PKA signaling is impaired in diabetes and suggests that treating hyperlipidemia is vital for proper cardiac signaling and function.
authors.affiliation: From the Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104 and the Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104.
authors.forename: Lee B
authors.initials: LB
authors.lastname: Bockus
authors.affiliation: From the Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104 and the Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104 kenneth-humphries@omrf.org.
authors.forename: Kenneth M
authors.identifier: http://orcid.org/0000-0002-6167-3175
authors.initials: KM
authors.lastname: Humphries
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000378:metabolism; D000818:Animals; D020134:Catalytic Domain; D000242:Cyclic AMP / Q000378:metabolism; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000378:metabolism*; D054746:Cyclic AMP-Dependent Protein Kinase Type II / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004195:Disease Models, Animal; D006333:Heart Failure / Q000503:physiopathology; D006352:Heart Ventricles / Q000473:pathology; D006439:Hemodynamics; D007773:Lactates / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction; D009206:Myocardium / Q000201:enzymology*; D032383:Myocytes, Cardiac / Q000378:metabolism; D025481:Phosphofructokinase-2 / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction
chemical_list: D007773:Lactates; D008055:Lipids; D015124:8-Bromo Cyclic Adenosine Monophosphate; D000242:Cyclic AMP; D025481:Phosphofructokinase-2; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; D054746:Cyclic AMP-Dependent Protein Kinase Type II
keywords: cardiac metabolism; cardiomyocyte; diabetes; heart; protein kinase A (PKA)