The incidence of congestive heart failure continues to increase in the United States despite significant advances in pharmacological therapy and novel devices. For this reason, there is an urgent need for novel therapies to treat heart failure. With a better understanding of the molecular mechanisms involved in the pathogenesis of heart failure, new targets are emerging. A key abnormality in heart failure is defective handling of calcium ions which has been shown to be related to abnormal sarcoplasmic reticulum (SR) function in cardiac myocytes. Reduced expression and activity of SERCA2a have been shown in multiple animal models of heart failure and in cardiomyocytes isolated from failing hearts explanted from patients undergoing transplantation. Restoring SERCA2a expression is associated with improved inotropy and lusitropy of isolated cardiomyocytes and with improved cardiac function in experimental models of heart failure. More recently, our group carried out a First-in-Man randomized gene therapy trial, using adeno-associated type 1vector carrying SERCA2a. In this trial, we found that AAV1.SERCA2a delivered to patients with advanced heart failure led to an improvement in the overall clinical status of patients with systolic heart failur, further highlighting the potential importance of SERCA2a as a therapeutic target in this condition. Our previous work, which led to the initiation of the clinical trials, was based on the premise that changes in the total protein expression of SERCA2a was critical in the calcium cycling abnormalities observed in heart failure. More recently, we found that the levels and activity of SERCA2a are modulated in parallel with the levels of a specific cytoplasmic protein SUMO1 (small ubiquitin-like modifier type 1). SUMOylation has been found to be involved in many cellular processes such as protein transport, gene transcription and DNA replication and repair. We found that SERCA2a and SUMO1 levels were both reduced in models of heart failure and in failing human myocardium. We showed that increasing SUMO1 levels led to improved hemodynamic performance and reduced mortality in a murine model of HF. We now propose to further characterize the molecular mechanisms of SUMO1 in regulating SERCA2a function and to evaluate the multiple pathways regulating SUMOylation of SERCA2a.
Heart failure is associated with abnormal calcium cycling which is related to a decrease in expression and a deficiency in the cardiac Sarcoplasmic Reticulum Calcium ATPase pump (SERCA2a). Recently, we have found that a small ubiquitin-related modifier, SUMO1, associates with SERCA2a in cardiac myocytes and modulates its function. In this proposal, we plan to study the molecular mechanisms of this novel protein SUMO1 and explore its suitability as a target for the treatment of heart failure.
| Hammoudi, Nadjib; Watanabe, Shin; Bikou, Olympia et al. (2018) Speckle-Tracking Echocardiographic Strain Analysis Reliably Estimates Degree of Acute LV Unloading During Mechanical LV Support by Impella. J Cardiovasc Transl Res : |
| Ceholski, Delaine K; Turnbull, Irene C; Kong, Chi-Wing et al. (2018) Functional and transcriptomic insights into pathogenesis of R9C phospholamban mutation using human induced pluripotent stem cell-derived cardiomyocytes. J Mol Cell Cardiol 119:147-154 |
| Oh, Jae Gyun; Watanabe, Shin; Lee, Ahyoung et al. (2018) miR-146a Suppresses SUMO1 Expression and Induces Cardiac Dysfunction in Maladaptive Hypertrophy. Circ Res 123:673-685 |
| Jeong, Dongtak; Yoo, Jimeen; Lee, Philyoung et al. (2018) miR-25 Tough Decoy Enhances Cardiac Function in Heart Failure. Mol Ther 26:718-729 |
| Watanabe, Shin; Fish, Kenneth; Bonnet, Guillaume et al. (2018) Echocardiographic and hemodynamic assessment for predicting early clinical events in severe acute mitral regurgitation. Int J Cardiovasc Imaging 34:171-175 |
| Stillitano, Francesca; Karakikes, Ioannis; Hajjar, Roger J (2017) Gene Transfer in Cardiomyocytes Derived from ES and iPS Cells. Methods Mol Biol 1521:183-193 |
| Watanabe, Shin; Leonardson, Lauren; Hajjar, Roger J et al. (2017) Cardiac Gene Delivery in Large Animal Models: Antegrade Techniques. Methods Mol Biol 1521:227-235 |
| Guénantin, Anne-Claire; Briand, Nolwenn; Capel, Emilie et al. (2017) Functional Human Beige Adipocytes From Induced Pluripotent Stem Cells. Diabetes 66:1470-1478 |
| Yoo, Jimeen; Hajjar, Roger J; Jeong, Dongtak (2017) Generation of Efficient miRNA Inhibitors Using Tough Decoy Constructs. Methods Mol Biol 1521:41-53 |
| Aguero, Jaume; Hadri, Lahouaria; Hammoudi, Nadjib et al. (2017) Inhaled Gene Transfer for Pulmonary Circulation. Methods Mol Biol 1521:339-349 |
Showing the most recent 10 out of 50 publications
