Rosuvastatin Reduces L-Type Ca2+ Current and Alters Contractile Function in Cardiac Myocytes via Modulation of β-Adrenergic Receptor Signaling

Abstract

Rosuvastatin is one of the most used statins to lower plasma cholesterol levels. Although previous studies have reported remarkable cardiovascular effects of rosuvastatin (RSV), the mechanisms of these effects are largely unknown. In this study, we investigated the acute effects of RSV on L-type Ca2+ currents and contractile function of ventricular myocytes under basal conditions and during β-adrenergic stimulation. The effects of RSV were investigated in freshly isolated adult rat ventricular myocytes. L-type Ca+2 currents and myocyte contractility were recorded using patch-clamp amplifier and sarcomere length detection system. All experimental recordings were performed at 36 ± 1 °C. L-type Ca+2 currents were significantly reduced with the administration of 1 μM RSV (~ 24%) and this reduction in Ca2+ currents was observed at almost all potential ranges applied. Suppression of L-type Ca2+ current by RSV was prevented by adenylyl cyclase (AC) and protein kinase A (PKA) inhibitors SQ 22536 and KT5720, respectively. However, inhibition of Rho-associated kinases (ROCKs) by Y-27632 or nitric oxide synthase (NOS) by L-NAME failed to circumvent the inhibitory effect of RSV. Finally, we examined the effect of RSV during β-adrenergic receptor stimulation by isoproterenol and observed that RSV significantly suppresses the β-adrenergic responses in both L-type Ca2+ currents and contraction parameters. In conclusion, RSV modulates the β-adrenergic signaling cascade and thereby mimics the impact of β-adrenergic receptor blockers in adult ventricular myocytes through modulation of the AC-cAMP-PKA pathway.

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Acknowledgement

This work was supported by Akdeniz University Research Projects Coordination Unit grant (Project number: TSA-2018-3209).

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SO designed and supervised the research and provided the final approval of the version to be published; NO and SU performed the experiments, analyzed the data, and contributed to the editing of the manuscript; TM and OE performed the experiments and analyzed the data. All authors discussed the results and commented on the manuscript.

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Correspondence to Semir Ozdemir.

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Ozturk, N., Uslu, S., Mercan, T. et al. Rosuvastatin Reduces L-Type Ca2+ Current and Alters Contractile Function in Cardiac Myocytes via Modulation of β-Adrenergic Receptor Signaling. Cardiovasc Toxicol 21, 422–431 (2021). https://doi.org/10.1007/s12012-021-09642-5

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Keywords

  • Rosuvastatin
  • Calcium current
  • Contractility
  • β-adrenergic signaling
  • Cardiac myocytes