Abstract P2006: S100A1 And STRIT1 Redundantly Governs Responsiveness Of The Heart To Hemodynamic Stress Via Modulation Of SERCA2a Activity

Abstract

Background & Objectives: SR Ca2+ load, which is sustained by SERCA2a pump activity, is a critical determinant for cardiac performance regulation & adaptation. Independent studies identified both S100A1 & STRIT1 as molecular enhancers of SERCA2a activity in the heart. S100A1 & STRIT1 decline in post-myocardial infarction hearts aggravated the transition to adverse cardiac remodelling & contractile failure. We therefore hypothesized that S100A1 & STRIT1 could act as independent but potentially redundant molecular switches for SERCA2a activity. Methods & Results: S100a1 knock-out (SKO) mice display no overt cardiac contractile or structural abnormalities in the absence of stress. RNA-seq transcriptomic analysis of left ventricle (LV) of SKO & wild type (WT) identified Strit1 amongst the top 3 most upregulated genes in SKO LV. We validated STRIT1 upregulation by RT-PCR as well as by immunoblotting (IB) that yielded a 15-fold increase compared with WT. Age lapse-resolved RT-PCR analysis showed Strit1 response to S100a1 knockout begins at post-partum day 5 & reaches plateau in adulthood. Next, we generated Strit1-S100a1 double knock out mice (StSKO), which showed only a mild decline in cardiac contractile performance. Interestingly, LV tissue serin-16 phospholamban (PLN) phosphorylation levels & PLNs pentameric state were found to be enhanced. WT, SKO & StSKO mice were then subjected to transaortic constriction (TAC) & followed for 60 days, which fully unmasked the mutually compensatory functions of S100A1 & STRIT1. In TAC-StSKO hearts showed significantly higher decline in LV %EF, significantly increased LV end-systolic volume & LV end-systolic diameter, & significantly increased cardiac hypertrophic growth together with concordant molecular markers. TAC-SKO mice did not show any decline in STRIT1 protein upregulation, while TAC-WT hearts showed a putatively compensatory increase in the S100A1/STRIT1 protein ratio. Conclusion: Our first results indicates that STRIT1 & S100A1 can act as compensatory molecular switches securing sufficient SERCA2a activity. As such, our study further sheds new light onto the novel concept of “molecular redundancy” to secure & protect cardiac key effector activities to cope with distinct hemodynamic stressors