Background and Objectives: SR Ca2+ load, which is sustained by SERCA2a pump activity, is a critical determinant for cardiac performance regulation and adaptation. Independent studies identified both S100A1 and STRIT1 as molecular enhancers of SERCA2a activity in the heart. S100A1 and STRIT1 decline in post-myocardial infarction hearts aggravated the transition to adverse cardiac remodeling and contractile failure. We therefore hypothesized that S100A1 and STRIT1 could act as independent but potentially redundant molecular switches for SERCA2a activity.

Methods and 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 and 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 and 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 and PLNs pentameric state were found to be enhanced. WT, SKO and StSKO mice were then subjected to transaortic constriction (TAC) and followed for 60 days, which fully unmasked the mutually compensatory functions of S100A1 and STRIT1. In TAC-StSKO hearts showed significantly higher decline in LV %EF, significantly increased LV end-systolic volume and LV end-systolic diameter, and 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 and 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 and protect cardiac key effector activities to cope with distinct hemodynamic stressors