title: Hyperamylinemia Increases IL-1β Synthesis in the Heart via Peroxidative Sarcolemmal Injury.
abstract: Hypersecretion of amylin is common in individuals with prediabetes, causes amylin deposition and proteotoxicity in pancreatic islets, and contributes to the development of type 2 diabetes. Recent studies also identified amylin deposits in failing hearts from patients with obesity or type 2 diabetes and demonstrated that hyperamylinemia accelerates the development of heart dysfunction in rats expressing human amylin in pancreatic β-cells (HIP rats). To further determine the impact of hyperamylinemia on cardiac myocytes, we investigated human myocardium, compared diabetic HIP rats with diabetic rats expressing endogenous (nonamyloidogenic) rat amylin, studied normal mice injected with aggregated human amylin, and developed in vitro cell models. We found that amylin deposition negatively affects cardiac myocytes by inducing sarcolemmal injury, generating reactive aldehydes, forming amylin-based adducts with reactive aldehydes, and increasing synthesis of the proinflammatory cytokine interleukin-1β (IL-1β) independently of hyperglycemia. These results are consistent with the pathological role of amylin deposition in the pancreas, uncover a novel contributing mechanism to cardiac myocyte injury in type 2 diabetes, and suggest a potentially treatable link of type 2 diabetes with diabetic heart disease. Although further studies are necessary, these data also suggest that IL-1β might function as a sensor of myocyte amylin uptake and a potential mediator of myocyte injury.
authors.affiliation: Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY.
authors.forename: Miao
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY.
authors.forename: Nirmal
authors.initials: N
authors.lastname: Verma
authors.affiliation: Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Peng
authors.affiliation: Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY.
authors.forename: Sarah
authors.initials: S
authors.lastname: Srodulski
authors.affiliation: Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky, Lexington, KY.
authors.forename: Andrew
authors.initials: A
authors.lastname: Morris
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY.
authors.forename: Martin
authors.initials: M
authors.lastname: Chow
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY.
authors.forename: Louis B
authors.initials: LB
authors.lastname: Hersh
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY.
authors.forename: Haining
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Internal Medicine, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.affiliation: Cardiovascular Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Margulies
authors.affiliation: Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY.
authors.forename: Sanda
authors.initials: S
authors.lastname: Despa
authors.affiliation: Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY f.despa@uky.edu.
authors.forename: Florin
authors.initials: F
authors.lastname: Despa
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D006801:Humans; D007120:Immunochemistry; D053583:Interleukin-1beta / Q000378:metabolism*; D058228:Islet Amyloid Polypeptide / Q000378:metabolism*; D008054:Lipid Peroxides / Q000378:metabolism*; D055432:Metabolomics; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012508:Sarcolemma / Q000378:metabolism*
chemical_list: D053583:Interleukin-1beta; D058228:Islet Amyloid Polypeptide; D008054:Lipid Peroxides