HuR-mediated posttranscriptional modification of Cx40 and coronary microvascular dysfunction in type 2 diabetes

Abstract Background Diabetic patients with coronary microvascular disease (CMD) exhibit higher cardiac mortality than patients without CMD. However, the molecular mechanism by which diabetes promotes CMD is poorly understood. RNA-binding protein HuR is a key regulator of mRNA stability and translation of many genes, and there is growing evidence showing the potential role of HuR in cardiovascular disease. In this study, we investigated the role of HuR and its target genes in the development of CMD in type 2 diabetic mice. Methods Type 2 diabetes was induced in male mice by a high-fat diet combined with a single injection of low-dose streptozotocin. We assessed coronary flow velocity reserve (CFVR, a determinant of coronary microvascular function) in vivo and isolated cardiac endothelial cells (CECs) from those mice for in vitro experiment. Coronary endothelial function was evaluated in the 3rd order of coronary arteries using a wire myograph. Human CECs from 4 control subjects and 4 diabetic patients were purchased from the company. Results Diabetic mice exhibited decreases in CFVR and capillary density in the left ventricle (LV). HuR protein levels in CECs were significantly lower in diabetic mice and diabetic patients than in the controls. Endothelial-specific HuR-KO mice also displayed significant reductions in CFVR and capillary density. By examining mRNA levels of 92 genes associated with endothelial function, we found that HuR, Cx40, and Nox4 levels were decreased in CECs from diabetic and HuR-KO mice in comparison to control mice. Cx40 protein level and HuR binding to Cx40 mRNA were downregulated in CECs from diabetic mice, and Cx40-KO mice exhibited decreased CFVR, attenuated endothelium-dependent relaxation, and reduced capillary density in the LV. Furthermore, endothelium-specific Cx40 overexpression ameliorated endothelial functions by augmenting endothelium-dependent relaxation and increasing capillary density in the LV, and resulted in the improvement of CFVR in diabetic mice. Conclusions These data suggest that decreased HuR, a specific mRNA binding protein that downregulates gap junction protein Cx40 in CECs, plays an important role in the development of coronary microvascular disease in diabetes. Restoration of Cx40 expression and function is potentially a novel therapeutic strategy for diabetic cardiovascular complications.

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Associations between Vitamin D and Type 2 Diabetes Mellitus: The Role of Vitamin D Receptor and Binding Protein

Journal of Diabetes Mellitus ◽

10.4236/jdm.2020.104018 ◽

2020 ◽

Vol 10 (04) ◽

pp. 222-235

Author(s):

Eman S. Arafat ◽

Inass M. Taha ◽

Shahad W. Kattan ◽

Nouf Abubakr Babteen ◽

Iman Fawzy

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Vitamin D ◽

Type 2 Diabetes Mellitus ◽

Vitamin D Receptor ◽

Binding Protein

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Synergy in Polymicrobial Infections in a Mouse Model of Type 2 Diabetes

Infection and Immunity ◽

10.1128/iai.73.9.6055-6063.2005 ◽

2005 ◽

Vol 73 (9) ◽

pp. 6055-6063 ◽

Cited By ~ 37

Author(s):

Matthew D. Mastropaolo ◽

Nicholas P. Evans ◽

Meghan K. Byrnes ◽

Ann M. Stevens ◽

John L. Robertson ◽

...

Keyword(s):

Type 2 Diabetes ◽

White Blood Cells ◽

In Vivo Model ◽

Diabetic Patients ◽

Diabetic Mice ◽

E Coli ◽

Polymicrobial Infections ◽

Young Mice

ABSTRACT Human diabetics frequently suffer delayed wound healing, increased susceptibility to localized and systemic infections, and limb amputations as a consequence of the disease. Lower-limb infections in diabetic patients are most often polymicrobial, involving mixtures of aerobic, facultative anaerobic, and anaerobic bacteria. The purpose of this study is to determine if these organisms contribute to synergy in polymicrobial infections by using diabetic mice as an in vivo model. The model was the obese diabetic mouse strain BKS.Cg-m +/+ Lepr db /J, a model of human type 2 diabetes. Young (5- to 6-week-old) prediabetic mice and aged (23- to 24-week-old) diabetic mice were compared. The mice were injected subcutaneously with mixed cultures containing Escherichia coli, Bacteroides fragilis, and Clostridium perfringens. Progression of the infection (usually abscess formation) was monitored by examining mice for bacterial populations and numbers of white blood cells at 1, 8, and 22 days postinfection. Synergy in the mixed infections was defined as a statistically significant increase in the number of bacteria at the site of injection when coinfected with a second bacterium, compared to when the bacterium was inoculated alone. E. coli provided strong synergy to B. fragilis but not to C. perfringens. C. perfringens and B. fragilis provided moderate synergy to each other but only in young mice. B. fragilis was anergistic (antagonistic) to E. coli in coinfections in young mice at 22 days postinfection. When age-matched nondiabetic mice (C57BLKS/J) were used as controls, the diabetic mice exhibited 5 to 35 times the number of CFU as did the nondiabetic mice, indicating that diabetes was a significant factor in the severity of the polymicrobial infections.

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O-GlcNAcase overexpression reverses coronary endothelial cell dysfunction in type 1 diabetic mice

AJP Cell Physiology ◽

10.1152/ajpcell.00069.2015 ◽

2015 ◽

Vol 309 (9) ◽

pp. C593-C599 ◽

Cited By ~ 26

Author(s):

Ayako Makino ◽

Anzhi Dai ◽

Ying Han ◽

Katia D. Youssef ◽

Weihua Wang ◽

...

Keyword(s):

Endothelial Cells ◽

Endothelial Dysfunction ◽

Endothelial Function ◽

Protein Modification ◽

Control Level ◽

Vascular Complications ◽

Capillary Density ◽

Diabetic Mice ◽

Endothelium Dependent Relaxation

Cardiovascular disease is the primary cause of morbidity and mortality in diabetes, and endothelial dysfunction is commonly seen in these patients. Increased O-linked N-acetylglucosamine ( O-GlcNAc) protein modification is one of the central pathogenic features of diabetes. Modification of proteins by O-GlcNAc ( O-GlcNAcylation) is regulated by two key enzymes: β- N-acetylglucosaminidase [ O-GlcNAcase (OGA)], which catalyzes the reduction of protein O-GlcNAcylation, and O-GlcNAc transferase (OGT), which induces O-GlcNAcylation. However, it is not known whether reducing O-GlcNAcylation can improve endothelial dysfunction in diabetes. To examine the effect of endothelium-specific OGA overexpression on protein O-GlcNAcylation and coronary endothelial function in diabetic mice, we generated tetracycline-inducible, endothelium-specific OGA transgenic mice, and induced OGA by doxycycline administration in streptozotocin-induced type 1 diabetic mice. OGA protein expression was significantly decreased in mouse coronary endothelial cells (MCECs) isolated from diabetic mice compared with control MCECs, whereas OGT protein level was markedly increased. The level of protein O-GlcNAcylation was increased in diabetic compared with control mice, and OGA overexpression significantly decreased the level of protein O-GlcNAcylation in MCECs from diabetic mice. Capillary density in the left ventricle and endothelium-dependent relaxation in coronary arteries were significantly decreased in diabetes, while OGA overexpression increased capillary density to the control level and restored endothelium-dependent relaxation without changing endothelium-independent relaxation. We found that connexin 40 could be the potential target of O-GlcNAcylation that regulates the endothelial functions in diabetes. These data suggest that OGA overexpression in endothelial cells improves endothelial function and may have a beneficial effect on coronary vascular complications in diabetes.

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Increased Expression of Meteorin-Like Hormone in Type 2 Diabetes and Obesity and Its Association with Irisin

Cells ◽

10.3390/cells8101283 ◽

2019 ◽

Vol 8 (10) ◽

pp. 1283 ◽

Cited By ~ 11

Author(s):

AlKhairi ◽

Cherian ◽

Abu-Farha ◽

Madhoun ◽

Nizam ◽

...

Keyword(s):

Type 2 Diabetes ◽

Plasma Levels ◽

Positive Association ◽

Diabetic Patients ◽

Metabolic Dysregulation ◽

Strong Positive Association ◽

Metabolic Biomarkers ◽

Diabetes And Obesity

Type 2 diabetes (T2D) is a growing pandemic associated with metabolic dysregulation and chronic inflammation. Meteorin-like hormone (METRNL) is an adipomyokine that is linked to T2D. Our objective was to evaluate the changes in METRNL levels in T2D and obesity and assess the association of METRNL levels with irisin. Overall, 228 Arab individuals were enrolled. Plasma levels of METRNL and irisin were assessed using immunoassay. Plasma levels of METRNL and irisin were significantly higher in T2D patients than in non-diabetic patients (p < 0.05). When the population was stratified based on obesity, METRNL and irisin levels were significantly higher in obese than in non-obese individuals (p < 0.05). We found a significant positive correlation between METRNL and irisin (r = 0.233 and p = 0.001). Additionally, METRNL and irisin showed significant correlation with various metabolic biomarkers associated with T2D and Obesity. Our data shows elevated METRNL plasma levels in individuals with T2D, further exacerbated with obesity. Additionally, a strong positive association was observed between METRNL and irisin. Further studies are necessary to examine the role of these proteins in T2D and obesity, against their ethnic background and to understand the mechanistic significance of their possible interplay.

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Role of retinol-binding protein 4 in the pathogenesis of Type 2 diabetes

Expert Review of Endocrinology & Metabolism ◽

10.1586/17446651.3.2.161 ◽

2008 ◽

Vol 3 (2) ◽

pp. 161-173 ◽

Cited By ~ 6

Author(s):

Kohzo Takebayashi ◽

Yoshimasa Aso ◽

Toshihiko Inukai

Keyword(s):

Type 2 Diabetes ◽

Binding Protein ◽

Retinol Binding Protein ◽

Retinol Binding Protein 4

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Endothelial Dysfunction: Is There a Hyperglycemia-Induced Imbalance of NOX and NOS?

International Journal of Molecular Sciences ◽

10.3390/ijms20153775 ◽

2019 ◽

Vol 20 (15) ◽

pp. 3775 ◽

Cited By ~ 23

Author(s):

Cesar A. Meza ◽

Justin D. La Favor ◽

Do-Houn Kim ◽

Robert C. Hickner

Keyword(s):

Type 2 Diabetes ◽

Cardiovascular Disease ◽

Blood Flow ◽

Endothelial Dysfunction ◽

Endothelial Function ◽

Vascular Dysfunction ◽

Vascular Complications ◽

Enzymatic Production

NADPH oxidases (NOX) are enzyme complexes that have received much attention as key molecules in the development of vascular dysfunction. NOX have the primary function of generating reactive oxygen species (ROS), and are considered the main source of ROS production in endothelial cells. The endothelium is a thin monolayer that lines the inner surface of blood vessels, acting as a secretory organ to maintain homeostasis of blood flow. The enzymatic production of nitric oxide (NO) by endothelial NO synthase (eNOS) is critical in mediating endothelial function, and oxidative stress can cause dysregulation of eNOS and endothelial dysfunction. Insulin is a stimulus for increases in blood flow and endothelium-dependent vasodilation. However, cardiovascular disease and type 2 diabetes are characterized by poor control of the endothelial cell redox environment, with a shift toward overproduction of ROS by NOX. Studies in models of type 2 diabetes demonstrate that aberrant NOX activation contributes to uncoupling of eNOS and endothelial dysfunction. It is well-established that endothelial dysfunction precedes the onset of cardiovascular disease, therefore NOX are important molecular links between type 2 diabetes and vascular complications. The aim of the current review is to describe the normal, healthy physiological mechanisms involved in endothelial function, and highlight the central role of NOX in mediating endothelial dysfunction when glucose homeostasis is impaired.

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ecNOS gene polymorphism is associated with endothelium-dependent vasodilation in Type 2 diabetes

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00653.2001 ◽

2002 ◽

Vol 283 (2) ◽

pp. H557-H561 ◽

Cited By ~ 22

Author(s):

Miyoko Komatsu ◽

Takahiko Kawagishi ◽

Masanori Emoto ◽

Tetsuo Shoji ◽

Atsuko Yamada ◽

...

Keyword(s):

Type 2 Diabetes ◽

Gene Polymorphism ◽

Endothelial Function ◽

Diabetic Patients ◽

Vascular Endothelial ◽

The Right ◽

Constitutive Nitric Oxide Synthase ◽

Oxide Synthase ◽

The Impact

The association between endothelial constitutive nitric oxide synthase (ecNOS) gene polymorphism and vascular endothelial function has not been clarified. We investigated the impact of ecNOS gene polymorphism on endothelial function in 95 patients with Type 2 diabetes (ecNOS genotype: 4b/b, n= 62; 4b/a, n = 30; 4a/a, n = 3). Flow-mediated (endothelium dependent, FMD) and nitroglycerin-induced (endothelium independent, NTG) vasodilations of the right brachial artery were studied using a phase-locked echotracking system. There were no significant differences in clinical characteristics among the ecNOS genotypes. The FMD was significantly lower in the patients with ecNOS4a allele than in those without ecNOS4a allele ( P< 0.05). Multiple regression analysis showed that ecNOS4a allele and mean blood pressure were significant independent determinants for reduced FMD in all patients ( R2 = 0.122, P = 0.0025). The ecNOS4a allele was an independent determinant for reduced FMD in smokers but not in nonsmokers. These results suggest that ecNOS4a allele is a genetic risk factor for endothelial dysfunction in diabetic patients, especially in smokers.

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Abstract 272: Hyperhomocysteinemia Potentiated the Impairment of Hydrogen Sulfide-induced Endothelium-derived Hyperpolarization-mediated Vascular Relaxation in Diabetic Db/db Mice

Circulation Research ◽

10.1161/res.117.suppl_1.272 ◽

2015 ◽

Vol 117 (suppl_1) ◽

Author(s):

Zhongjian Cheng ◽

Xiaohua Jiang ◽

Xinggui Shen ◽

Pu Fang ◽

Raj Kishore ◽

...

Keyword(s):

Hydrogen Sulfide ◽

Endothelial Function ◽

Mesenteric Arteries ◽

Diabetic Patients ◽

Diabetic Mice ◽

Vascular Relaxation ◽

Type 2 Diabetic Patients ◽

Plasma Thcy ◽

Calcium Activated Potassium Channel

Background: Cumulative evidence indicates that plasma homocysteine (Hcy) level is positively correlated with cardiovascular mortality in Type 2 diabetic patients. Aims: To explore the effects and mechanisms of elevated plasma Hcy level[[Unable to Display Character: ―]] hyperhomocysteinemia (HHcy) on endothelial function in db/db mice. Methods and Results: HHcy was induced in diabetic db/db and non-diabetic db/+ mice fed with a high methionine diet (HM, 2% methionine) for 8 weeks (plasma tHcy=54.31±5.4 and 34.21±4.15 μM). Endothelial function was examined in small mesenteric arteries (SMA) using myographs. In non-diabetic mice, HHcy did not change vascular relaxation to acetylcholine (Ach); whereas, nitric oxide (NO)- and prostacyclin (PGI2)-mediated relaxation to Ach were impaired. Interestingly, endothelium-derived hyperpolarization factor (EDHF)-mediated relaxation to Ach was improved. In diabetic mice, HHcy potentiated the impairment of NO-, PGI2- and EDHF-mediated relaxation to Ach. Moreover, sodium hydrogen sulfide (NaHS), a donor of hydrogen sulfide (H2S), induced EDHF-mediated relaxation which was impaired in diabetic mice and potentiated by HHcy. NS309, a non-specific calcium-activated potassium channel (Kca) activator, significantly improved H2S- and Ach-induced EDHF-mediated relaxation in diabetic mice with HHcy. Tram-34, an intermediate conductance Kca (IK) blocker, but not small conductance Kca blocker apamin, diminished HHcy-induced impairment of EDHF-mediated relaxation in diabetic mice, suggesting that IK inactivation plays a major role. Free sulfide was decreased in plasma and SMA of diabetic mice which was potentiated with HHcy. Superoxide generation was increased and potentiated by HHcy in lung ECs from diabetic mice. Moreover, PEG-SOD improved vascular relaxation in diabetic mice with HHcy. Finally, tyrosine nitration of IK was increased in human cardiac microvascular endothelial cells (ECs) treated with either D-glucose (25 mM) or DL-Hcy (500 μM) for 48h, which was potentiated by a combination of D-glucose and DL-Hcy. Conclusions: H2S is a major EDHF in resistant arteries in mouse. H2S-contributed EDHF-mediated vascular relaxation was impaired in diabetes and was potentiated by HHcy via oxidative stress and IK inactivation.

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Role of probiotics for the treatment of peri-implant mucositis in patients with and without type-2 diabetes mellitus

Journal of Oral Implantology ◽

10.1563/aaid-joi-d-20-00302 ◽

2020 ◽

Author(s):

Fawaz Alqahtani ◽

Maha Alshaikh ◽

Abid Mehmood ◽

Nasser Alqhtani ◽

Fahad Alkhtani ◽

...

Keyword(s):

Type 2 Diabetes ◽

Diabetic Patients ◽

Treatment Procedure ◽

Inflammatory Parameters ◽

Probing Depth ◽

Crestal Bone Loss ◽

Group 2

The hypothesis was that probiotic therapy (PT) does not offer additional benefits to mechanical debridement (MD) for treatment of diabetic subjects with peri-implant mucositis (PM). This study compared the influence of PT as an adjunct to MD for the treatment of PM in type2 diabetic and non-diabetic patients over a 12-month follow-up period. Patients with and without type-2 diabetes were encompassed. Based upon treatment-procedure, PM patients were categorized into 2 groups: (a) Non-surgical + PT; and (b) Group-2: Non-surgical MD alone. Demographics and education statuses were recorded. Gingival (GI) and plaque (PI) indices, crestal bone loss (CBL) and probing depth (PD were measured at baseline and after 6- and 12-months. Significant differences were detected with P<0.01. The HbA1c was significantly higher in diabetic patients at all time durations than patients without type-2 diabetes (P<0.001). Baseline GI, PI, PD and CBL) were comparable in all groups. In patients with type-2-diabetes, there was no difference in PI, GI, PD and CBL at 6- and 12-months’ follow-up. In patients without type-2 diabetes, there was a significant reduction in PI (P<0.01), GI (P<0.01), and PD (P<0.01) at 6-months and 1-year follow-up than their values at baseline. In patients without type-2 diabetes, MD with or without adjunct PT reduces soft tissue inflammatory parameters in patients with PM.

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