Olmesartan Restores <i>LMNA</i> Function in Haploinsufficient Cardiomyocytes
Abstract
BACKGROUND: Gene mutations are responsible for a sizeable proportion of cases of heart failure. However, the number of patients with any specific mutation is small. Repositioning of existing US Food and Drug Administration–approved compounds to target specific mutations is a promising approach to efficient identification of new therapies for these patients. METHODS: The National Institutes of Health Library of Integrated Network-Based Cellular Signatures database was interrogated to identify US Food and Drug Administration–approved compounds that demonstrated the ability to reverse the transcriptional effects of LMNA knockdown. Top hits from this screening were validated in vitro with patient-specific induced pluripotent stem cell–derived cardiomyocytes combined with force measurement, gene expression profiling, electrophysiology, and protein expression analysis. RESULTS: Several angiotensin receptor blockers were identified from our in silico screen. Of these, olmesartan significantly elevated the expression of sarcomeric genes and rate and force of contraction and ameliorated arrhythmogenic potential. In addition, olmesartan exhibited the ability to reduce phosphorylation of extracellular signal–regulated kinase 1 in LMNA -mutant induced pluripotent stem cell–derived cardiomyocytes. CONCLUSIONS: In silico screening followed by in vitro validation with induced pluripotent stem cell–derived models can be an efficient approach to identifying repositionable therapies for monogenic cardiomyopathies.
Article Details
Authors (9)
Eric J. Kort
DeVos Cardiovascular Research Program, Fredrik Meijer Heart and Vascular Institute, Spectrum Health and Van Andel Institute, Grand Rapids, MI (E.J.K., J.F., E.E., S.J.).
Nazish Sayed
Stanford Cardiovascular Institute, CA (D.T., A.M., Y.L., R.V., N.B., S.R.Z., C.J., I.Y.C., N.S., J.C.W.).
Chun Liu
State Key Laboratory of Fine Chemicals, Frontier Science Center for Smart Materials, School of Chemical Engineering, Dalian University of Technology, Linggong Road 2, Dalian 116024, China
Gema Mondéjar-Parreño
Stanford Cardiovascular Institute (G.M.-P., S.R.Z., X.C., Y.L., J.Y.Y., J.W.S.J., D.W., N.S., J.C.W.).
Jens Forsberg
DeVos Cardiovascular Research Program, Fredrik Meijer Heart and Vascular Institute, Spectrum Health and Van Andel Institute, Grand Rapids, MI (E.J.K., J.F., E.E., S.J.).
Emily Eugster
Sean M. Wu
Joseph C. Wu
Stefan Jovinge
Scania University Sweden, Lund, Sweden