Faculty Bibliography

Background: The United Arab Emirates (UAE) is experiencing increasing rates of obesity, type 2 diabetes (T2D) and its complications. We tested if soluble levels of cell surface-cleaved RAGE (sRAGE) or endogenous secretory RAGE (esRAGE), the product of alternative mRNA splicing of AGER, are associated with T2D and obesity in the UAE.
Method(s): A case-control study was performed in the Diabetes, Endocrinology and General Medical Clinics of the Sheikh Khalifa Medical City in Abu Dhabi. 216 T2D subjects and 215 controls (mean age 57.4+/-12.1 vs. 50.7+/-15.4 years, respectively) were enrolled. Plasma sRAGE and esRAGE levels, anthropomorphic characteristics and routine chemistries were measured. The relationship between sRAGE and esRAGE with obesity and T2D status was tested using a linear regression model.
Result(s): Univariate analyses comparing T2D case and control subjects revealed differences in sRAGE (1,033+/-545.3 vs. 1,169+/-664.1 pg/ml, respectively; p=0.02) but not esRAGE. Covariate adjustment revealed that differences in sRAGE were significant after correction for age and sex and additionally for waist-hip ratio (WHR); total cholesterol (TC), HDL; hsCRP; Vit D; or triglyceride (TG) levels separately. In cases or controls, we tested associations of body mass index (BMI) or WHR with sRAGE and esRAGE. In controls but not T2D cases, sRAGE and esRAGE were significantly associated with BMI, after correction for age and sex and additionally for eGFR; blood pressure; TC, HDL; hsCRP; Vit D; creatinine; TG and HbA1c in a combined model. In the case of WHR, in controls and T2D cases, there were no associations with sRAGE, but only in T2D cases, WHR was associated with esRAGE after correction for age and sex and blood pressure; TC, HDL; hsCRP, HbA1c, creatinine; TG, eGFR, Vit D and TG in a combined model.
Conclusion(s): Levels of sRAGE but not esRAGE distinguish T2D case vs. controls in the UAE population. Genetic and unique obesity-dependent factors may underlie lack of association between esRAGE in cases vs. controls, which may affect vulnerability to T2D and its complications in the UAE

INTRODUCTION: The consequences of chronic disease are vast and unremitting; hence, understanding the pathogenic mechanisms mediating such disorders holds promise to identify therapeutics and diminish the consequences. The ligands of the receptor for advanced glycation end products (RAGE) accumulate in chronic diseases, particularly those characterized by inflammation and metabolic dysfunction. Although first discovered and reported as a receptor for advanced glycation end products (AGEs), the expansion of the repertoire of RAGE ligands implicates the receptor in diverse milieus, such as autoimmunity, chronic inflammation, obesity, diabetes, and neurodegeneration. Areas covered: This review summarizes current knowledge regarding the ligand families of RAGE and data from human subjects and animal models on the role of the RAGE axis in chronic diseases. The recent discovery that the cytoplasmic domain of RAGE binds to the formin homology 1 (FH1) domain, DIAPH1, and that this interaction is essential for RAGE ligand-stimulated signal transduction, is discussed. Finally, we review therapeutic opportunities targeting the RAGE axis as a means to mitigate chronic diseases. Expert commentary: With the aging of the population and the epidemic of cardiometabolic disease, therapeutic strategies to target molecular pathways that contribute to the sequelae of these chronic diseases are urgently needed. In this review, we propose that the ligand/RAGE axis and its signaling nexus is a key factor in the pathogenesis of chronic disease and that therapeutic interruption of this pathway may improve quality and duration of life.

Aldose reductase (AR: human, AKR1B1; mouse, AKR1B3), the first enzyme in the polyol pathway, plays a key role in mediating myocardial ischemia/reperfusion (I/R) injury. In earlier studies, using transgenic mice broadly expressing human AKR1B1 to human-relevant levels, mice devoid of Akr1b3, and pharmacological inhibitors of AR, we demonstrated that AR is an important component of myocardial I/R injury and that inhibition of this enzyme protects the heart from I/R injury. In this study, our objective was to investigate if AR modulates the beta-catenin pathway and consequent activation of mesenchymal markers during I/R in the heart. To test this premise, we used two different experimental models: in vivo, Akr1b3 null mice and wild type C57BL/6 mice (WT) were exposed to acute occlusion of the left anterior descending coronary artery (LAD) followed by recovery for 48 hours or 28 days, and ex-vivo, WT and Akr1b3 null murine hearts were perfused using the Langendorff technique (LT) and subjected to 30 min of global (zero-flow) ischemia followed by 60 min of reperfusion. Our in vivo results reveal reduced infarct size and improved functional recovery at 48 hours in mice devoid of Akr1b3 compared to WT mice. We demonstrate that the cardioprotection observed in Akr1b3 null mice was linked to acute activation of the beta-catenin pathway and consequent activation of mesenchymal markers and genes linked to fibrotic remodeling. The increased activity of the beta-catenin pathway at 48 hours of recovery post-LAD was not observed at 28 days post-infarction, thus indicating that the observed increase in beta-catenin activity was transient in the mice hearts devoid of Akr1b3. In ex vivo studies, inhibition of beta-catenin blocked the cardioprotection observed in Akr1b3 null mice hearts. Taken together, these data indicate that AR suppresses acute activation of beta-catenin and, thereby, blocks consequent induction of mesenchymal markers during early reperfusion after myocardial ischemia. Inhibition of AR might provide a therapeutic opportunity to optimize cardiac remodeling after I/R injury.

Acetylation of proteins as a post-translational modification is gaining rapid acceptance as a cellular control mechanism on par with other protein modification mechanisms such as phosphorylation and ubiquitination. Through genetic manipulations and evolving proteomic technologies, identification and consequences of transcription factor acetylation is beginning to emerge. In this review, we summarize the field and discuss newly unfolding mechanisms and consequences of transcription factor acetylation in normal and stressed hearts. This article is part of a Special Issue entitled: The role of post-translational protein modifications on heart and vascular metabolism edited by Jason R.B. Dyck & Jan F.C. Glatz.

Post-translational modification of proteins imparts diversity to protein functions. The process of glycation represents a complex set of pathways that mediates advanced glycation endproduct (AGE) formation, detoxification, intracellular disposition, extracellular release, and induction of signal transduction. These processes modulate the response to hyperglycemia, obesity, aging, inflammation, and renal failure, in which AGE formation and accumulation is facilitated. It has been shown that endogenous anti-AGE protective mechanisms are thwarted in chronic disease, thereby amplifying accumulation and detrimental cellular actions of these species. Atop these considerations, receptor for advanced glycation endproducts (RAGE)-mediated pathways downregulate expression and activity of the key anti-AGE detoxification enzyme, glyoxalase-1 (GLO1), thereby setting in motion an interminable feed-forward loop in which AGE-mediated cellular perturbation is not readily extinguished. In this review, we consider recent work in the field highlighting roles for glycation in obesity and atherosclerosis and discuss emerging strategies to block the adverse consequences of AGEs. This article is part of a Special Issue entitled: The role of post-translational protein modifications on heart and vascular metabolism edited by Jason R.B. Dyck & Jan F.C. Glatz.

Drug development (DD) is a multidisciplinary process that spans the translational continuum, yet remains an understudied entity in medical schools and biomedical science institutes. In response to a growing interest and unmet need, we implemented a DD course series that details identification of viable molecular targets, clinical trial design, intellectual property, and marketing. Enrollment is open to faculty, postdoctoral trainees, and MD, PhD, and MS students. After 2 years, 37 students and 23 students completed the fall and spring courses, respectively. Pre/post-surveys demonstrated gained knowledge across course topics, with mean survey scores increased by 66% (p < 0.001) after each course. Lectures for each course were consistently rated highly, with a mean course rating of 4.1/5. Through this program, trainees will have a more innovative approach toward identification of therapeutic targets and modalities. Furthermore, they will learn to integrate technology and biomedical informatics to find creative solutions in the DD process.

Histone deacetylase 3 (HDAC3), a chromatin-modifying enzyme, requires association with the deacetylase-containing domain (DAD) of the nuclear receptor corepressors NCOR1 and SMRT for its stability and activity. Here, we show that aldose reductase (AR), the rate-limiting enzyme of the polyol pathway, competes with HDAC3 to bind the NCOR1/SMRT DAD. Increased AR expression leads to HDAC3 degradation followed by increased PPARgamma signaling, resulting in lipid accumulation in the heart. AR also downregulates expression of nuclear corepressor complex cofactors including Gps2 and Tblr1, thus affecting activity of the nuclear corepressor complex itself. Though AR reduces HDAC3-corepressor complex formation, it specifically derepresses the retinoic acid receptor (RAR), but not other nuclear receptors such as the thyroid receptor (TR) and liver X receptor (LXR). In summary, this work defines a distinct role for AR in lipid and retinoid metabolism through HDAC3 regulation and consequent derepression of PPARgamma and RAR.

Our studies have shown the cytoplasmic domain of the receptor for advanced glycation endproducts (RAGE) binds to the formin molecule, diaphanous-1 (mDia1). mDia1 is a member of the formin family of intracellular molecules involved in cellular migration which act as effectors of Rho GTPase signaling. In RAGE-expressing cells devoid of Drf1 (gene encoding mDia1), incubation with RAGE ligands failed to generate reactive oxygen species or activate key signaling cellular stress pathways. Here, we sought to determine if mDia1 plays key roles in a murine model of diabetic nephropathy (DN). Our preliminary data reveal that mDia1 expression is increased in human and murine diabetic podocytes and parietal epithelial cells in a diffuse and global pattern compared to age-matched controls. Furthermore, expression patterns of mDia1 are highly analogous to those of RAGE. While the role of RAGE has been shown to play a key role in the development of DN, the potential contribution of mDia1 has yet to be elucidated. Therefore, we tested the hypothesis that mDia1 contributes to the development and progression of diabetic renal disease in a murine model. Male wild-type and Drf1-null (WT, Drf1KO; all in the C57BL/6 background) mice were rendered diabetic at 6 weeks of age with streptozotocin and sacrificed after 3 or 6 months of diabetes. Kidneys were harvested and processed for histology and gene expression and stained with periodic-acid Schiff (PAS) and semi-quantitative scoring was used to determine the degree of mesangial sclerosis by average findings in >100 glomeruli/mouse (scale 0-3+; 0=absent, 1=mild, 2=moderate, 3=severe). Glomerular basement membrane (GBM) thickness and podocyte foot process effacement (FPE) were measured by ultrastructural analysis (>8 glomeruli/mouse). Gene expression of inflammatory markers (transforming growth factor beta; Tgfb, interleukin 6; Il6, and monocyte chemoattractant protein 1; Ccl2) were assessed by quantitative real time PCR using RNA prepared from whole kidney cortex and normalized to beta-actin. This preliminary study suggests that deletion of Drf1 in mice results in a substantial protection against indices of DN by reducing podocyte effacement, inflammation and fibrosis in type 1 DM. View this table: In this window In a new window Table 1 Histological and microscopic observations show that mDiaKO mice have a reduced GBM, less podocyte FPE and a decrease in mesangial sclerosis compared to WT mice after 6 months of diabetes. (Table Presented)