Abstract
BackgroundWe previously demonstrated the small heat shock protein, HSPB1, to prevent tachycardia remodeling in in vitro and in vivo models for Atrial Fibrillation (AF). To gain insight into its mechanism of action, we examined the protective effect of all 10 members of the HSPB family on tachycardia remodeling. Furthermore, modulating effects of HSPB on RhoA GTPase activity and F-actin stress fiber formation were examined, as this pathway was found of prime importance in tachycardia remodeling events and the initiation of AF.Methods and ResultsTachypacing (4 Hz) of HL-1 atrial myocytes significantly and progressively reduced the amplitude of Ca2+ transients (CaT). In addition to HSPB1, also overexpression of HSPB6, HSPB7 and HSPB8 protected against tachypacing-induced CaT reduction. The protective effect was independent of HSPB1. Moreover, tachypacing induced RhoA GTPase activity and caused F-actin stress fiber formation. The ROCK inhibitor Y27632 significantly prevented tachypacing-induced F-actin formation and CaT reductions, showing that RhoA activation is required for remodeling. Although all protective HSPB members prevented the formation of F-actin stress fibers, their mode of action differs. Whilst HSPB1, HSPB6 and HSPB7 acted via direct prevention of F-actin formation, HSPB8-protection was mediated via inhibition of RhoA GTPase activity.ConclusionOverexpression of HSPB1, as well as HSPB6, HSPB7 and HSPB8 independently protect against tachycardia remodeling by attenuation of the RhoA GTPase pathway at different levels. The cardioprotective role for multiple HSPB members indicate a possible therapeutic benefit of compounds able to boost the expression of single or multiple members of the HSPB family.
Highlights
Atrial Fibrillation (AF) is the most common sustained and progressive clinical tachycardia in the population and it significantly contributes to cardiovascular morbidity and mortality [1]
Overexpression of HSPB1, as well as HSPB6, HSPB7 and HSPB8 independently protect against tachycardia remodeling by attenuation of the RhoA GTPase pathway at different levels
As observed before [3], tachypacing at 4 Hz of HL-1 myocytes resulted in a significant and progressive reduction in Ca2+ transients (CaT) (Figure S1), which was attenuated by HSPB1 (Figure 1B,C Movie S1, Movie S2, Movie S3)
Summary
Atrial Fibrillation (AF) is the most common sustained and progressive clinical tachycardia in the population and it significantly contributes to cardiovascular morbidity and mortality [1]. We recently identified one specific member of the heat shock protein (HSP) family, HSPB1, to protect against AF-induced remodeling [2;3]. Because of the known protective actions of HSPBs on actin cytoskeleton, we examined their effect on tachypacinginduced RhoA GTPase pathway, including RhoA GTPase activity and related F-actin stress fiber formation. HSPB1, HSPB6 and HSPB7 were found to directly prevent F-actin stress fiber formation, whereas HSPB8-protection was mediated via inhibition of upstream RhoA GTPase activity. We previously demonstrated the small heat shock protein, HSPB1, to prevent tachycardia remodeling in in vitro and in vivo models for Atrial Fibrillation (AF). Modulating effects of HSPB on RhoA GTPase activity and F-actin stress fiber formation were examined, as this pathway was found of prime importance in tachycardia remodeling events and the initiation of AF
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