Novel HSF-1 mimetics as therapeutics to restore proteostasis in Atrial Fibrillation

Bianca JJM Brundel1,3, Femke Hoogstra-Berneds1,3, Irma Kuipers3, Andre Heeres2, Herman Steen3, Robert H Henning1. 1UMCG, Clinical Pharmacology, 9713AV, The Netherlands, 2Syncom, Research ChemistryPostcode, 9747 AT, Groningen, The Netherlands, 3Nyken, Research, 9713 GX Groningen, The Netherlands

Background: Atrial Fibrillation (AF) is the most common clinical tachyarrhythmia associated with significant morbidity and mortality affecting about 30 million Europeans and North Americans by 2050. Important risk factors for AF include obesity, metabolic syndrome, hypertension and increasing age. AF is a persistent disease, caused by progressive derailment of proteostasis resulting in structural remodeling of cardiomyocytes and contractile dysfunction. The progressive nature of AF hampers effective functional conversion to sinus rhythm and explains the limited effect of current drug therapies. Recently, we showed that induction of Heat Shock Proteins (HSPs) by Heat Shock Factor 1 (HSF-1) mimetics protect against remodeling of cardiomyocytes in cellular, Drosophila melanogaster and animal experimental models. Disadvantage of current HSF-1 mimetics, such as geranylgeranylacetone (GGA), is their high LogP value necessitating high dosages. Therefore, the aim of the current study was to identify novel potent HSP-inducing compounds, with improved pharmaco-chemical properties, which protect against induction of AF.

Methods: Various (n=83) GGA-derivatives were synthesized and tested in HL-1 cardiomyocytes (10µM, 6 hrs incubation), which were pretreated with a mild heat shock (430C 10 min, 10 min recovery 370C) to activate HSF-1. It was observed that 30 GGA-derivatives induced a significant increase in expression of HSP70 (>15 fold, Western blot) and HSP25, HSP90, HSP40 (all HSF-1 related, qPCR), but not Grp78 (HSF-2 related, qPCR), compared to non-treated heat shocked cardiomyocytes. Their effect was comparable or improved compared to GGA (range 89%-167%). Next, HL-1 cardiomyocytes were pretreated with the 13 most potent HSP70-inducing HSF-1 mimetics for 8 hrs, followed by 8 hrs tachypacing (5 Hz) or normal pacing (1 Hz) and contractile function was determined by measuring calcium transients (CaT). Tachypacing significantly reduced the amplitude of CaT (-64±4% compared to 1 Hz) and 7 HSF-1 mimetics attenuated CaT reduction completely.

Conclusion: Novel HSF-1 mimetics were identified with improved HSP-inducing, cardioprotective and pharmaco-chemical properties compared to GGA. Ultimately, these HSF-1 mimetics may prevent AF occurrence and expansion of the structural remodeling during AF, resulting in improved outcome of cardioversion and/or delay in progression towards permanent AF.