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Abstract
Background
The heat shock protein (HSP) inducer, geranylgeranylacetone (GGA), was previously found to protect against atrial fibrillation (AF) remodeling in experimental model systems. Clinical application of GGA in AF is limited, due to low systemic concentrations owing to the hydrophobic character of GGA.
Objectives
To identify novel HSP-inducing compounds, with improved physicochemical properties, that prevent contractile dysfunction in experimental model systems for AF.
Methods
Eighty-one GGA-derivatives were synthesized and explored for their HSP-inducing properties by assessment of HSP expression in HL-1 cardiomyocytes pretreated with or without a mild heat shock (HS), followed by incubation with 10 µM GGA or GGA-derivative. Subsequently, the most potent HSP-inducers were tested for preservation of calcium transient (CaT) amplitudes or heart wall contraction in pretreated tachypaced HL-1 cardiomyocytes (with or without HSPB1 siRNA) and Drosophilas, respectively. Finally, CaT recovery in tachypaced HL-1 cardiomyocytes posttreated with GGA or protective GGA-derivatives was determined.
Results
Thirty GGA-derivatives significantly induced HSPA1A expression after HS, and seven showed exceeding HSPA1A expression compared to GGA. GGA and nine GGA-derivatives protected significantly from tachypacing (TP)-induced CaT loss, which was abrogated by HSPB1 suppression. GGA and four potent GGA-derivatives protected against heart wall dysfunction after TP compared to non-paced control Drosophilas. Of these compounds, GGA and three GGA-derivatives induced a significant restoration from CaT loss after TP of HL-1 cardiomyocytes.
Conclusion
We identified novel GGA-derivatives with improved physicochemical properties compared to GGA. GGA-derivatives, particularly GGA*-59, boost HSP expression resulting in prevention and restoration from TP-induced remodeling, substantiating their role as novel therapeutics in clinical AF.
Acknowledgments
This work was supported by the Dutch Heart Foundation (2013T144 and 2013T096) and the Netherlands Cardiovascular Research Initiative and Dutch Heart Foundation (CVON2014-40 DOSIS and CVON-STW2016-14728 AFFIP), the European Community, European Fund for Regional Development (Operationeel Programma Noord-Nederland 2007–2012, OP-EFRO), the Life Sciences & Health-Impulse grant (40-43100-98-008), and the Province of Groningen, Innovative Action-program Groningen (IAG3).
Author contributions
All authors contributed toward data analysis, drafting and critically revising the paper, gave final approval of the version to be published, and agreed to be accountable for all aspects of the work.
Disclosure
Jean-Paul G Seerden, Lizette Loen, and Andre Heeres are employees of Syncom BV. Herman Steen is the founder and CEO of Chaperone Pharma BV, a pharmaceutical company engaged in clinical development of HSP boosting drugs. The authors report no other conflicts of interest in this work.