SERCA2a superinhibition by human phospholamban triggers electrical and structural remodeling in mouse hearts

Abstract

Phospholamban (PLN), the reversible inhibitor of the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a), is a key regulator of myocyte Ca(2+) cycling with a significant role in heart failure. We previously showed that the single amino acid difference between human and mouse PLN results in increased inhibition of Ca(2+) cycling and cardiac remodeling and attenuated stress responses in transgenic mice expressing the human PLN (hPLN) in the null background. Here we dissect the molecular and electrophysiological processes triggered by the superinhibitory hPLN in the mouse. Using a multidisciplinary approach, we performed global gene expression analysis, electrophysiology, and mathematical simulations on hPLN mice. We identified significant changes in a series of Na(+) and K(+) homeostasis genes/proteins (including Kcnd2, Scn9a, Slc8a1) and ionic conductance (including L-type Ca(2+) current, Na(+)/Ca(2+) exchanger, transient outward K(+) current). Simulation analysis suggests that this electrical remodeling has a critical role in rescuing cardiac function by improving sarcoplasmic reticulum Ca(2+) load and overall Ca(2+) dynamics. Furthermore, multiple structural and transcription factor gene expression changes indicate an ongoing structural remodeling process, favoring hypertrophy and myogenesis while suppressing apoptosis and progression to heart failure. Our findings expand current understanding of the hPLN function and provide additional insights into the downstream implications of SERCA2a superinhibition in the mammalian heart.

TGF-β1–induced phospholamban expression alters esophageal smooth muscle cell contraction in patients with eosinophilic esophagitis

“…Both null and missense mutations in the human phospholamban gene cause cardiomyopathy, heart failure, cardiomyocyte enlargement, decreased contractile function, and electrophysiological remodeling (28, 39, 40). PLN has been described in the murine gastric smooth muscle as well as in the airway of beta receptor overexpressing mice.…”

Characterizing Phospholamban to Sarco(endo)plasmic Reticulum Ca2+-ATPase 2a (SERCA2a) Protein Binding Interactions in Human Cardiac Sarcoplasmic Reticulum Vesicles Using Chemical Cross-linking

“…Subsequently, in a study in which human PLB was expressed in transgenic mice, Kranias and co-workers concluded that lysine at position 27 makes PLB superinhibitory, inducing heart failure and cardiac remodeling in transgenic mice (38,39). Because of these effects observed in mice, novel functions for PLB in human myocardium were proposed (38,39). However, in the present study, we determined that human PLB (with Lys 27 ) inhibits SERCA2a activity to the same extent as canine PLB, which has Asn 27 .…”

Downregulation of GSTK1 Is a Common Mechanism Underlying Hypertrophic Cardiomyopathy

“…These findings suggest that compensatory hypertrophy is unlikely to be the cause of HCM induced by mutation of sarcomeric genes ( Ashrafian et al, 2011 ). PLN regulates sarcoplasmic reticulum Ca 2+ cycling in the heart through inhibition of ATPase sarcoplasmic/endoplasmic reticulum Ca 2+ transporting 2 (ATP2A2) ( Wang et al, 2011 ). Mutation of PLN causing superinhibition of ATP2A2 can cause HCM ( Wang et al, 2011 ).…”

“…PLN regulates sarcoplasmic reticulum Ca 2+ cycling in the heart through inhibition of ATPase sarcoplasmic/endoplasmic reticulum Ca 2+ transporting 2 (ATP2A2) ( Wang et al, 2011 ). Mutation of PLN causing superinhibition of ATP2A2 can cause HCM ( Wang et al, 2011 ). Haploinsufficiency of ATP2A2 can also cause HCM, possibly through mitochondrial dysfunction ( Prasad et al, 2015 ), suggesting that mutation of PLN causing HCM may impair mitochondrial function.…”