Uncoupling proteins as a therapeutic target to protect the diabetic heart. (November 2018)

• Record Type: Journal Article
• Authors: Dludla, Phiwayinkosi V.; Nkambule, Bongani B.; Tiano, Luca; Louw, Johan; Jastroch, Martin; Mazibuko-Mbeje, Sithandiwe E.
• Is Part Of: Pharmacological research. Volume 137(2018)
• Page Start: 11
• Page End: 24
• Publication Date: 2018-11
• Subjects: ACC acetyl-CoA carboxylase -- ACE angiotensin-converting enzyme -- AICAR 5-aminoimidazole-4-carboxamide ribonucleotide -- ALDH2 aldehyde dehydrogenase 2 -- AMPK 5' AMP-activated protein kinase -- ATP adenosine triphosphate -- Bax Bcl-2-like protein 4 -- BNIP3 Bcl-2 interacting protein 3 -- DCM diabetic cardiomyopathy -- eNOS endothelial nitric oxide synthase -- FFA free fatty acid -- GDP guanosine diphosphate -- GLP-1 glucagon-like peptide-1 -- GLUT4 glucose transporter 4 -- HAECs human aortic endothelial cells -- HO-1 heme oxygenase 1 -- HOMA-IR homeostatic model assessment-insulin resistance -- IR ischemia-reperfusion -- JAK Janus kinase -- MAPK mitogen-activated protein kinase -- MeSH medical subject heading -- mPTP mitochondrial permeability transition pore -- MST1 macrophage-stimulating protein 1 -- NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells -- NRF2 nuclear factor (erythroid-derived 2)-like 2 -- LETF Otsuka Long–Evans Tokushima Fatty -- PDK pyruvate dehydrogenase kinase -- PGC-1α peroxisome proliferator-activated receptor gamma coactivator 1-alpha -- PKC protein kinase C -- PPAR peroxisome proliferator-activated receptor -- SNRK SNF-related serine/threonine-protein kinase -- SIRT NAD-dependent deacetylase sirtuin -- SREBP-1 sterol regulatory element-binding protein 1 -- STAT signal transducer and activator of transcription; Diabetes mellitus -- Cardiomyopathy -- Oxidative stress -- Uncoupling proteins; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2018.09.013
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: Myocardial remodeling and dysfunction caused by accelerated oxidative damage is a widely reported phenomenon within a diabetic state. Altered myocardial substrate preference appears to be the major cause of enhanced oxidative stress-mediated cell injury within a diabetic heart. During this process, exacerbated free fatty acid flux causes an abnormal increase in mitochondrial membrane potential leading to the overproduction of free radical species and subsequent cell damage. Uncoupling proteins (UCPs) are expressed within the myocardium and can protect against free radical damage by modulating mitochondrial respiration, leading to reduced production of reactive oxygen species. Moreover, transgenic animals lacking UCPs have been shown to be more susceptible to oxidative damage and display reduced cardiac function when compared to wild type animals. This suggests that tight regulation of UCPs is necessary for normal cardiac function and in the prevention of diabetes-induced oxidative damage. This review aims to enhance our understanding of the pathophysiological mechanisms relating to the role of UCPs in a diabetic heart, and further discuss known pharmacological compounds and hormones that can protect a diabetic heart through the modulation of UCPs.