Modulation of cardiac voltage-activated K+ currents by glypican 1 heparan sulfate proteoglycan.

BACKGROUND

Glypican 1 (Gpc1) is a heparan sulfate proteoglycan attached to the cell membrane via a glycosylphosphatidylinositol anchor, where it holds glycosaminoglycans nearby. We have recently shown that Gpc1 knockout (Gpc1-/-) mice feature decreased systemic blood pressure. To date, none has been reported regarding the role of Gpc1 on the electrical properties of the heart and specifically, in regard to a functional interaction between Gpc1 and voltage-gated K+ channels.

METHODS

We used echocardiography and in vivo (electrocardiographic recordings) and in vitro (patch clamping) electrophysiology to study mechanical and electric properties of mice hearts. We used RT-PCR to probe K+ channels' gene transcription in heart tissue.

RESULTS

Gpc1-/- hearts featured increased cardiac stroke volume and preserved ejection fraction. Gpc1-/- electrocardiograms showed longer QT intervals, abnormalities in the ST segment, and delayed T waves, corroborated by longer action potentials in isolated ventricular cardiomyocytes. In voltage-clamp, these cells showed decreased Ito and IK voltage-activated K+ current densities. Moreover, IK showed activation at less negative voltages, but a higher level of inactivation at a given membrane potential. Kcnh2 and Kcnq1 voltage-gated K+ channels subunits' transcripts were remarkably more abundant in heart tissues from Gpc1-/- mice, suggesting that Gpc1 may interfere in the steps between transcription and translation in these cases.

CONCLUSION

Our data reveals an unprecedented connection between Gpc1 and voltage-gated K+ channels expressed in the heart and this knowledge contributes to the understanding of the role of this HSPG in cardiac function which may play a role in the development of cardiovascular disease.