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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Adhikari, Bishow B
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Icahn School of Medicine at Mount Sinai
Internal Medicine/Medicine
Schools of Medicine
New York
United States
Zip Code
Chen, Jiqiu; Hammoudi, Nadjib; Benard, Ludovic et al. (2016) The Probability of Inconstancy in Assessment of Cardiac Function Post-Myocardial Infarction in Mice. Cardiovasc Pharm Open Access 5:
Evrard, Solene M; Lecce, Laura; Michelis, Katherine C et al. (2016) Endothelial to mesenchymal transition is common in atherosclerotic lesions and is associated with plaque instability. Nat Commun 7:11853
Lee, Ahyoung; Oh, Jae Gyun; Gorski, Przemek A et al. (2016) Post-translational Modifications in Heart Failure: Small Changes, Big Impact. Heart Lung Circ 25:319-24
Jeong, Dongtak; Lee, Min-Ah; Li, Yan et al. (2016) Matricellular Protein CCN5 Reverses Established Cardiac Fibrosis. J Am Coll Cardiol 67:1556-68
Jang, Seung Pil; Oh, Jae Gyun; Kang, Dong Hoon et al. (2016) A Decoy Peptide Targeted to Protein Phosphatase 1 Attenuates Degradation of SERCA2a in Vascular Smooth Muscle Cells. PLoS One 11:e0165569
Chamberlain, Kyle; Riyad, Jalish Mahmud; Weber, Thomas (2016) Expressing Transgenes That Exceed the Packaging Capacity of Adeno-Associated Virus Capsids. Hum Gene Ther Methods 27:1-12
Kho, Changwon; Lee, Ahyoung; Jeong, Dongtak et al. (2015) Small-molecule activation of SERCA2a SUMOylation for the treatment of heart failure. Nat Commun 6:7229
Chen, Gaopeng; Li, Sen; Karakikes, Ioannis et al. (2015) Phospholamban as a crucial determinant of the inotropic response of human pluripotent stem cell-derived ventricular cardiomyocytes and engineered 3-dimensional tissue constructs. Circ Arrhythm Electrophysiol 8:193-202
Gorski, Przemek A; Ceholski, Delaine K; Hajjar, Roger J (2015) Altered myocardial calcium cycling and energetics in heart failure-a rational approach for disease treatment. Cell Metab 21:183-94
Nonnenmacher, Mathieu E; Cintrat, Jean-Christophe; Gillet, Daniel et al. (2015) Syntaxin 5-dependent retrograde transport to the trans-Golgi network is required for adeno-associated virus transduction. J Virol 89:1673-87

Showing the most recent 10 out of 26 publications