TY - JOUR
T1 - Modulation of cardiac voltage-activated K+ currents by glypican 1 heparan sulfate proteoglycan
AU - Souza, Diego Santos
AU - Chignalia, Andreia Zago
AU - Carvalho-de-Souza, Joao Luis
N1 - Funding Information: This study was supported by funds from the Department of Anesthesiology at the University of Arizona and by the American Heart Association (CDA Grant # 850700/2021 [AZC] ). Publisher Copyright: © 2022 Elsevier Inc.
PY - 2022/11/1
Y1 - 2022/11/1
N2 - 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.
AB - 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.
KW - Delayed rectifiers
KW - Glypican 1
KW - Hypertension
KW - Long QT (LQT)
KW - Protein-protein interaction
KW - Transient outward current
KW - Voltage-activated K currents
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U2 - 10.1016/j.lfs.2022.120916
DO - 10.1016/j.lfs.2022.120916
M3 - Article
C2 - 36049528
SN - 0024-3205
VL - 308
JO - Life Sciences
JF - Life Sciences
M1 - 120916
ER -