Faculty Bibliography

Aims/UNASSIGNED:The transformation of the United Arab Emirates (UAE) from a semi-nomadic to a high income society has been accompanied by increasing rates of obesity and Type 2 diabetes mellitus. We examined if the AGE-RAGE (receptor for advanced glycation endproducts) axis is associated with obesity and diabetes mellitus in the pilot phase of the UAE Healthy Futures Study (UAEHFS). Methods/UNASSIGNED:517 Emirati subjects were enrolled and plasma/serum levels of AGE, carboxy methyl lysine (CML)-AGE, soluble (s)RAGE and endogenous secretory (es)RAGE were measured along with weight, height, waist and hip circumference (WC/HC), blood pressure, HbA1c, Vitamin D levels and routine chemistries. The relationship between the AGE-RAGE axis and obesity and diabetes mellitus was tested using proportional odds models and linear regression. Results/UNASSIGNED:After covariate adjustment, AGE levels were significantly associated with diabetes status. Levels of sRAGE and esRAGE were associated with BMI and levels of sRAGE were associated with WC/HC. Conclusions/UNASSIGNED:The AGE-RAGE axis is associated with diabetes status and obesity in this Arab population. Prospective serial analysis of this axis may identify predictive biomarkers of obesity and cardiometabolic dysfunction in the UAEHFS.

The biochemical, ionic, and signaling changes that occur within cardiomyocytes subjected to ischemia are exacerbated by reperfusion; however, the precise mechanisms mediating myocardial ischemia/reperfusion (I/R) injury have not been fully elucidated. The receptor for advanced glycation end-products (RAGE) regulates the cellular response to cardiac tissue damage in I/R, an effect potentially mediated by the binding of the RAGE cytoplasmic domain to the diaphanous-related formin, DIAPH1. The aim of this study was to investigate the role of DIAPH1 in the physiological response to experimental myocardial I/R in mice. After subjecting wild-type mice to experimental I/R, myocardial DIAPH1 expression was increased, an effect that was echoed following hypoxia/reoxygenation (H/R) in H9C2 and AC16 cells. Further, compared to wild-type mice, genetic deletion of Diaph1 reduced infarct size and improved contractile function after I/R. Silencing Diaph1 in H9C2 cells subjected to H/R downregulated actin polymerization and serum response factor-regulated gene expression. Importantly, these changes led to increased expression of sarcoplasmic reticulum Ca2+ ATPase and reduced expression of the sodium calcium exchanger. This work demonstrates that DIAPH1 is required for the myocardial response to I/R, and that targeting DIAPH1 may represent an adjunctive approach for myocardial salvage after acute infarction.

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.

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.

With advanced aging, there is a decline in innate cardiovascular function. This decline is not general in nature. Instead, specific changes occur that impact the basic cardiovascular function, which include alterations in biochemical pathways and ion channel function. This review focuses on a particular ion channel that couple the latter two processes, namely the KATP channel, which opening is promoted by alterations in intracellular energy metabolism. We show that the intrinsic properties of the KATP channel changes with advanced aging and argue that the channel can be further modulated by biochemical changes. The importance is widespread, given the ubiquitous nature of the KATP channel in the cardiovascular system where it can regulate processes as diverse as cardiac function, blood flow and protection mechanisms against superimposed stress, such as cardiac ischemia. We highlight questions that remain to be answered before the KATP channel can be considered as a viable target for therapeutic intervention.

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.

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.

Omega-3 fatty acids (n-3 FA) are bioactive nutrients exerting cardioprotective effects. In our previous study, we showed that acute n-3 FA emulsion administration after myocardial ischemia/reperfusion (I/R) injury provides cardioprotection by preserving cardiac function and decreasing infarct size. To address molecular mechanisms responsible for their cardioprotective effects we focused on two main pathways: lipid metabolism pathways and Ca²⁺ signaling, both playing a crucial role during early reperfusion in the metabolic and functional recovery of post-ischemic myocardium. C57BL/6 murine hearts were perfused using Langendorff technique and the administration of n-3 triglyceride emulsion (300mgTG/100ml) was performed during the reperfusion. We then studied lipid metabolism and Ca²⁺ signaling. We first investigated whether acute treatment with n-3 FA emulsion could modulate lipase activity. However, either myocardial ATGL or HSL expression was not altered by n-3 FA administration during I/R injury, demonstrating that the uptake of n-3 FA did not involve lipase-mediated pathways. AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor (PPAR) are critical regulators of lipid metabolism. We then examined whether the activities of these molecules were coordinately regulated by n-3 FA. After ischemic injury, n-3 FA induced phosphorylation of AMPK (p<0.05); in contrast, PPARalpha showed no changes in protein expression after n-3 FA administration. I/R injury also alters Ca²⁺ homeostasis through several mechanisms. Na⁺/Ca²⁺ exchanger (NCX) activity increases cytosolic Ca²⁺, causing cell damage. Also, in I/R conditions sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA2a) dysfunction impairs myocardial contractility and Ca²⁺ handling. Thus, we questioned whether NCX and SERCA2a might be potential targets for n-3 FA. n-3 FA administration after ischemic injury increased both mRNA and protein levels of SERCA2a by 60% (p<0.05). n-3 FA administration significantly decreased protein level of NCX by 50% (p<0.05), with no effect on its transcript level. Our results suggest that n-3 FA partially affect lipid metabolism by activating AMPK and regulate intracellular Ca²⁺ homeostasis through their influence on SERCA2a and NCX modulations in I/R conditions