Abstract
The sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) and phospholamban (PLN) complex regulates heart relaxation through its removal of cytosolic Ca2+ during diastole. Dysfunction of this complex has been related to many heart disorders and is therefore a key pharmacological target. There are currently no therapeutics that directly target either SERCA or PLN. It has been previously reported that single-stranded DNA binds PLN with strong affinity and relieves inhibition of SERCA in a length-dependent manner. In the current article, we demonstrate that RNAs and single-stranded oligonucleotide analogs, or xeno nucleic acids (XNAs), also bind PLN strongly (Kd <10 nm) and relieve inhibition of SERCA. Affinity for PLN is sequence-independent. Relief of PLN inhibition is length-dependent, allowing SERCA activity to be restored incrementally. The improved in vivo stability of XNAs offers more realistic pharmacological potential than DNA or RNA. We also found that microRNAs (miRNAs) 1 and 21 bind PLN strongly and relieve PLN inhibition of SERCA to a greater extent than a similar length random sequence RNA mixture. This may suggest that miR-1 and miR-21 have evolved to contain distinct sequence elements that are more effective at relieving PLN inhibition than random sequences.
Highlights
Diac Disease (CUPID) trials, drug development targeting specific proteins remains an essential, complimentary effort [5,6,7]
RNA Sequences Bind Phospholamban with Low Nanomolar Kd Reversing sarco(endo)plasmic reticulum Ca2ϩ-ATPase (SERCA) Inhibition—Previously, we found that ssDNA of varying lengths could relieve the inhibition of SERCA
Because non-coding RNAs are abundant in cardiomyocytes, we assayed whether RNA sequences would interact with PLN and reverse SERCA inhibition (Figs. 1 and 2)
Summary
MiRNAs are involved both in cardiogenesis [14, 15] and in disease including: diabetic cardiomyopathy, hypertrophy, ischemia, and electrical remodeling [16,17,18,19,20,21,22] Recent developments in both therapeutic inhibition and enhancement of miRNA function have demonstrated great promise for counteracting cardiac diseases [22, 23]. We report that many XNAs bind PLN with similar strong affinity to what was found previously for SPIDRs [12] These molecules, which are tunable by length, would allow clinicians to match the reversal of SERCA inhibition to the severity of the disease. Our results suggest that endogenous, non-coding miRNAs may play a more complex role in cardiac regulation than previously thought, targeting SERCA-PLN function via direct physical interactions
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