Circulating levels of mitochondrial uncoupling protein 2, but not prohibitin, are lower in humans with type 2 diabetes and correlate with brachial artery flow-mediated dilation

Abstract Background Excessive reactive oxygen species from endothelial mitochondria in type 2 diabetes individuals (T2DM) may occur through multiple related mechanisms, including production of mitochondrial reactive oxygen species (mtROS), inner mitochondrial membrane (Δψm) hyperpolarization, changes in mitochondrial mass and membrane composition, and fission of the mitochondrial networks. Inner mitochondrial membrane proteins uncoupling protein-2 (UCP2) and prohibitin (PHB) can favorably impact mtROS and mitochondrial membrane potential (Δψm). Circulating levels of UCP2 and PHB could potentially serve as biomarker surrogates for vascular health in patients with and without T2DM. Methods Plasma samples and data from a total of 107 individuals with (N = 52) and without T2DM (N = 55) were included in this study. Brachial artery flow mediated dilation (FMD) was measured by ultrasound. ELISA was performed to measure serum concentrations of PHB1 and UCP2. Mitochondrial membrane potential was measured from isolated leukocytes using JC-1 dye. Results Serum UCP2 levels were significantly lower in T2DM subjects compared to control subjects (3.01 ± 0.34 vs. 4.11 ± 0.41 ng/mL, P = 0.04). There were no significant differences in levels of serum PHB. UCP2 levels significantly and positively correlated with FMDmm (r = 0.30, P = 0.03) in T2DM subjects only and remained significant after multivariable adjustment. Within T2DM subjects, serum PHB levels were significantly and negatively correlated with UCP2 levels (ρ = − 0.35, P = 0.03). Conclusion Circulating UCP2 levels are lower in T2DM patients and correlate with endothelium-dependent vasodilation in conduit vessels. UCP2 could be biomarker surrogate for overall vascular health in patients with T2DM and merits additional investigation.

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Uncoupling Protein 2: A Key Player and a Potential Therapeutic Target in Vascular Diseases

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/7348372 ◽

2017 ◽

Vol 2017 ◽

pp. 1-11 ◽

Cited By ~ 22

Author(s):

Giorgia Pierelli ◽

Rosita Stanzione ◽

Maurizio Forte ◽

Serena Migliarino ◽

Marika Perelli ◽

...

Keyword(s):

Therapeutic Target ◽

Mitochondrial Membrane ◽

Uncoupling Protein ◽

Target Organ Damage ◽

Vascular Diseases ◽

Organ Damage ◽

Metabolic Energy ◽

Uncoupling Protein 2 ◽

Inner Mitochondrial Membrane ◽

Ucp2 Gene

Uncoupling protein 2 (UCP2) is an inner mitochondrial membrane protein that belongs to the uncoupling protein family and plays an important role in lowering mitochondrial membrane potential and dissipating metabolic energy with prevention of oxidative stress accumulation. In the present article, we will review the evidence that UCP2, as a consequence of its roles within the mitochondria, represents a critical player in the predisposition to vascular disease development in both animal models and in humans, particularly in relation to obesity, diabetes, and hypertension. The deletion of the UCP2 gene contributes to atherosclerosis lesion development in the knockout mice, also showing significantly shorter lifespan. The UCP2 gene downregulation is a key determinant of higher predisposition to renal and cerebrovascular damage in an animal model of spontaneous hypertension and stroke. In contrast, UCP2 overexpression improves both hyperglycemia- and high-salt diet-induced endothelial dysfunction and ameliorates hypertensive target organ damage in SHRSP. Moreover, drugs (fenofibrate and sitagliptin) and several vegetable compounds (extracts from Brassicaceae, berberine, curcumin, and capsaicin) are able to induce UCP2 expression level and to exert beneficial effects on the occurrence of vascular damage. As a consequence, UCP2 becomes an interesting therapeutic target for the treatment of common human vascular diseases.

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Uncoupling protein-2 accumulates rapidly in the inner mitochondrial membrane during mitochondrial reactive oxygen stress in macrophages

Biochimica et Biophysica Acta (BBA) - Bioenergetics ◽

10.1016/j.bbabio.2007.11.006 ◽

2008 ◽

Vol 1777 (2) ◽

pp. 118-129 ◽

Cited By ~ 53

Author(s):

Tindaro M. Giardina ◽

James H. Steer ◽

Susan Z.Y. Lo ◽

David A. Joyce

Keyword(s):

Mitochondrial Membrane ◽

Uncoupling Protein ◽

Reactive Oxygen ◽

Uncoupling Protein 2 ◽

Inner Mitochondrial Membrane ◽

Oxygen Stress

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Abstract 243: The Role of Reactive Oxygen Species in Hyperglycemia-Induced Attenuation of Anesthetic Preconditioning in Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Circulation Research ◽

10.1161/res.111.suppl_1.a243 ◽

2012 ◽

Vol 111 (suppl_1) ◽

Author(s):

Scott Canfield ◽

Danielle Twaroski ◽

Xiaowen Bai ◽

Chika Kikuchi ◽

Zeljko J Bosnjak

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Membrane Potential ◽

Lactate Dehydrogenase ◽

Mitochondrial Membrane ◽

Oxygen Species ◽

Anesthetic Preconditioning ◽

Induced Pluripotent ◽

Type 2 Diabetic

Anesthetic Preconditioning (APC) protects the myocardium from ischemia/reperfusion injury. The cardioprotective effects of APC is diminished or even eliminated in individuals with diabetes mellitus and/or hyperglycemia. The development of patient-specific induced pluripotent stem cells and their differentiation capability has provided us with an in vitro model to study the inefficiency of APC in these individuals.To investigate the underlying mechanisms involved in the attenuation of APC in both diabetic individuals and in hyperglycemia we utilized cardiomyocytes derived from Type 2 diabetic patient and healthy individual iPSCs, (T2DM-iPSCs and N-iPSCs, respectively). Contracting cardiomyocytes were dissociated and selected by the expression of green fluorescent protein under the transcriptional control of myosin light chain-2v. Cardiomyocytes were exposed to varying glucose concentrations (5, 11, and 25 mM). Lactate dehydrogenase (LDH) release was measured using a colorimetric cytotoxicity assay kit and read spectrophotometrically. Mitochondrial membrane potential and reactive oxygen species (ROS) generation were measured with confocal microscopy. APC reduced oxidative stress-induced lactate dehydrogenase (LDH) release in cardiomyocytes derived from both N-iPSCs- and T2DM-iPSCs in 5 and 11 mM glucose concentrations, but not in 25 mM glucose. Baseline membrane potential was similar between non-diabetic- and Type 2 diabetic-derived cardiomyocytes; however 25 mM glucose hyperpolarized the mitochondrial membrane potential. T2DM-iPSC-derived cardiomyocytes had an increase in ROS baseline levels compared to N-iPSC-derived cardiomyocytes. Additionally, high glucose concentrations increased oxidative stress-induced ROS production compared to lower glucose conditions in both cell lines. Our preliminary data shows that high glucose generates excessive ROS and hyperpolarizes the mitochondrial membrane and may contribute to the inefficiency of diabetic and/or hyperglycemic individuals to be anesthetically preconditioned. By utilizing human iPSC-derived cardiomyocytes we can begin to understand the inability of hyperglycemic and diabetic individuals to be anesthetically preconditioned.

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Association Study of Candidate Gene Uncoupling Protein 2 (UCP2) with Type 2 Diabetes Mellitus in the Different Population Groups of Jammu Region

Biosciences Biotechnology Research Asia ◽

10.13005/bbra/2751 ◽

2019 ◽

Vol 16 (2) ◽

pp. 351-357

Author(s):

Sunil Raina ◽

Roopali Fotra

Keyword(s):

Diabetes Mellitus ◽

Metabolic Disorders ◽

Uncoupling Protein ◽

Molecular Genetic ◽

Promoter Polymorphism ◽

Uncoupling Protein 2 ◽

Population Groups ◽

Allelic Odds Ratio

Diabetes Mellitus is a group of metabolic disorders characterized by hyperglycaemic resulting from the defects of insulin secretion, insulin action or both. The present study was conducted in order to know the molecular genetic cause of the T2DM patients belonging to the Jammu region of J&K State. Many genes have been known to be linked with the onset and progression of the T2DM therefore the present data represents the role of one of the genes Uncoupling protein 2 (UCP2) known to be strongly associated with T2DM was selected. A total of 250 confirmed cases & controls samples belonging to four population groups (Hindu, Muslim, Sikh & Christians) of Jammu region were also screened for UCP2 -866G/A promoter polymorphism (rs659366). The allelic odds ratio (OR) as observed for UCP2 -866G/A polymorphism in the four population groups showed significant association with Muslim & Sikh population groups. The study undertaken supports the findings of the previous investigations and thus is an addition to the existing literatute in support of UCP2 and T2DM.

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PD142: Uncoupling protein 2 attenuates production of reactive oxygen species and interleukin-8 in THP-1 cells stimulated with Porphyromonas gingivalis -derived lipopolysaccharide

Journal Of Clinical Periodontology ◽

10.1111/jcpe.145_12914 ◽

2018 ◽

Vol 45 ◽

pp. 92-92

Keyword(s):

Reactive Oxygen Species ◽

Porphyromonas Gingivalis ◽

Uncoupling Protein ◽

Reactive Oxygen ◽

Interleukin 8 ◽

Uncoupling Protein 2 ◽

Oxygen Species

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Uncoupling Protein 2 Drives Myocardial Dysfunction in Murine Models of Septic Shock

BioMed Research International ◽

10.1155/2019/9786101 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10 ◽

Cited By ~ 1

Author(s):

Rong Tang ◽

Ping-ping Qi ◽

Yan-song Liu ◽

Liu Jia ◽

Rui-jin Liu ◽

...

Keyword(s):

Membrane Potential ◽

Mitochondrial Membrane Potential ◽

Cardiac Dysfunction ◽

Mitochondrial Membrane ◽

Viral Vector ◽

Therapeutic Potential ◽

Uncoupling Protein ◽

Myocardial Dysfunction ◽

Multiorgan Failure ◽

Uncoupling Protein 2

Cardiac dysfunction is a major component of sepsis-induced multiorgan failure in critical care units. Uncoupling protein 2 (UCP2) involves immune response, regulation of oxidative stress, and maintenance of mitochondrial membrane potential as well as energy production. However, whether and how UCP2 plays roles in the development of septic cardiac dysfunction are largely unknown. Here, intraperitoneal injection of LPS significantly activated UCP2 expression accompanied by a significant decrease of cardiac function and caused a significantly lower survival rate in mice. Of note, knockdown of UCP2 through a cardiotropic adenoassociated viral vector carrying a short hairpin RNA (shRNA) specifically targeting the UCP2 evoked resistance to LPS-triggered septic cardiac dysfunction and lethality in vivo. Moreover, UCP2 deficiency ameliorated the reduced levels of intracellular ATP in the LPS-challenged heart tissues and preserved mitochondrial membrane potential loss in primary adult mouse cardiomyocytes in LPS-challenged animals. Mechanistically, we confirmed that the inhibition of UCP2 promoted autophagy in response to LPS, as shown by an increase in LC3II and a decrease in p62. At last, the autophagy inhibitor 3-MA abolished UCP2 knockdown-afforded cardioprotective effects. Those results indicate that UCP2 drives septic cardiac dysfunction and that the targeted induction of UCP2-mediated autophagy may have important therapeutic potential.

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