Poster abstracts

Poster number 70 submitted by Chinna Venkata

Inhibition of eIF5A hypusination attenuates fibroblast activation and cardiac fibrosis

Kadiam C Venkata Subbaiah (Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine & Dentistry), Jiangbin Wu (Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine & Dentistry), Peng Yao (Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine & Dentistry)

Abstract:
Cardiac fibrosis is a primary contributor to heart failure (HF) and sudden death, and is considered to be an important target for HF therapy1. Cardiac fibroblast (CF) activation, including proliferation, survival, and extracellular matrix (ECM) production, is central to the initiation and maintenance of fibrotic scaring in cardiac fibrosis. However, drug molecules that target CF activation remain limited in treating cardiac fibrosis. Eukaryotic translation initiation factor 5A (eIF5A)2,3, the only protein to contain hypusine, has been found to be a modulator of cell proliferation and apoptosis4. Indeed, depletion of eIF5A or inhibition of eIF5A hypusination antagonizes diabetes-induced inflammation5 and modulates mitochondrial function6. In this study we found that increased hypusinated eIF5A protein levels were associated with cardiac fibrosis and heart dysfunction in experimental myocardial infarction (MI) mouse models. Ciclopirox (CPX), an FDA approved antifungal drug, inhibits the deoxyhypusine hydroxylase (DOHH) enzyme that is required for the hypusine formation in eIF5A. Results from both preventive and reversal mouse models suggested that CPX treatment significantly reduced MI-driven cardiac fibrosis and improved cardiac function. In vitro studies of isolated mouse primary CFs and cultured human CFs revealed that knockdown (KD) of eIF5A using lentiviral shRNA significantly abolished TGF- induced CF activation, proliferation, and collagen protein expression compared to scrambled shRNA treated cells. Proteomic analyses from mouse and human CFs suggested that KD of eIF5A significantly down-regulates the expression of proline-proline dipeptidyl motif containing proteins. Gene ontology analysis revealed that these target proteins are enriched in extracellular matrix, extracellular exosome, and cell adhesion pathways. Our findings are relevant to human heart disease as increased hypusinated eIF5A levels were observed in heart samples of dilated cardiomyopathy and ischemic heart failure patients in comparison to healthy subjects. Together, these results suggest that eIF5A could be a novel and promising therapeutic target in treating cardiac fibrosis and human heart failure.

References:
1 Gulati, A. et al.. JAMA 309, 896-908, doi:10.1001/jama.2013.1363 (2013).
2 Schuller, A. P., Wu, C. C., Dever, T. E., Buskirk, A. R. & Green, R.. Mol Cell 66, 194-205 e195, doi:10.1016/j.molcel.2017.03.003 (2017).
3 Manjunath, H. et al.. Cell Rep 29, 3134-3146 e3136, doi:10.1016/j.celrep.2019.10.129 (2019).
4 Mathews, M. B. & Hershey, J. W.. Biochim Biophys Acta 1849, 836-844, doi:10.1016/j.bbagrm.2015.05.002 (2015).

Keywords: eIF5A, Ciclopirox, Cardiac fibrosis