title: Interplay of oxidative, nitrosative/nitrative stress, inflammation, cell death and autophagy in diabetic cardiomyopathy.
abstract: Diabetes is a recognized risk factor for cardiovascular diseases and heart failure. Diabetic cardiovascular dysfunction also underscores the development of diabetic retinopathy, nephropathy and neuropathy. Despite the broad availability of antidiabetic therapy, glycemic control still remains a major challenge in the management of diabetic patients. Hyperglycemia triggers formation of advanced glycosylation end products (AGEs), activates protein kinase C, enhances polyol pathway, glucose autoxidation, which coupled with elevated levels of free fatty acids, and leptin have been implicated in increased generation of superoxide anion by mitochondria, NADPH oxidases and xanthine oxidoreductase in diabetic vasculature and myocardium. Superoxide anion interacts with nitric oxide forming the potent toxin peroxynitrite via diffusion limited reaction, which in concert with other oxidants triggers activation of stress kinases, endoplasmic reticulum stress, mitochondrial and poly(ADP-ribose) polymerase 1-dependent cell death, dysregulates autophagy/mitophagy, inactivates key proteins involved in myocardial calcium handling/contractility and antioxidant defense, activates matrix metalloproteinases and redox-dependent pro-inflammatory transcription factors (e.g. nuclear factor kappaB) promoting inflammation, AGEs formation, eventually culminating in myocardial dysfunction, remodeling and heart failure. Understanding the complex interplay of oxidative/nitrosative stress with pro-inflammatory, metabolic and cell death pathways is critical to devise novel targeted therapies for diabetic cardiomyopathy, which will be overviewed in this brief synopsis. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases.
authors.affiliation: Laboratory of Physiological Studies, National Institutes of Health/NIAAA, Bethesda, MD, USA; Cardiometabolic Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.
authors.forename: Zoltán V
authors.initials: ZV
authors.lastname: Varga
authors.affiliation: Cardiometabolic Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Giricz
authors.affiliation: Department of Intensive Care Medicine BH 08-621-University Hospital Medical Center 1011 LAUSANNE Switzerland.
authors.forename: Lucas
authors.initials: L
authors.lastname: Liaudet
authors.affiliation: Department of Surgery and Center for Immunity and Inflammation, Rutgers NJ Medical School, USA.
authors.forename: György
authors.initials: G
authors.lastname: Haskó
authors.affiliation: Cardiometabolic Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary; Pharmahungary Group, Szeged, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Ferdinandy
authors.affiliation: Laboratory of Physiological Studies, National Institutes of Health/NIAAA, Bethesda, MD, USA. Electronic address: pacher@mail.nih.gov.
authors.forename: Pál
authors.initials: P
authors.lastname: Pacher
mesh_terms: D000818:Animals; D001343:Autophagy; D058065:Diabetic Cardiomyopathies / Q000473:pathology* / Q000628:therapy; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D058990:Molecular Targeted Therapy; D015538:Nitrosation; D018384:Oxidative Stress
keywords: Autophagy; Diabetic cardiomyopathy; Oxidative stress; Protein oxidation