Oxidative stress in early metabolic syndrome impairs cardiac RyR2 and SERCA2a activity and modifies the interplay of these proteins during Ca²⁺ waves

Abstract

We investigated how oxidative stress (OS) alters Ca²⁺ handling in ventricular myocytes in early metabolic syndrome (MetS) in sucrose-fed rats. The effects of N-acetyl cysteine (NAC) or dl-Dithiothreitol (DTT) on systolic Ca²⁺ transients (SCaTs), diastolic Ca²⁺ sparks (CaS) and Ca²⁺ waves (CaW), recorded by confocal techniques, and L-type Ca²⁺ current (I_Ca), assessed by whole-cell patch clamp, were evaluated in MetS and Control cells. MetS myocytes exhibited decreased SCaTs and CaS frequency but unaffected CaW propagation. In Control cells, NAC/DTT reduced RyR2/SERCA2a activity blunting SCaTs, CaS frequency and CaW propagation, suggesting that basal ROS optimised Ca²⁺ signalling by maintaining RyR2/SERCA2a function and that these proteins facilitate CaW propagation. Conversely, NAC/DTT in MetS recovered RyR2/SERCA2a function, improving SCaTs and CaS frequency, but unexpectedly decreasing CaW propagation. We hypothesised that OS decreases RyR2/SERCA2a activity at early MetS, and while decreased SERCA2a favours CaW propagation, diminished RyR2 restrains it.

Keywords:

• Cardiac metabolic syndrome
• ryanodine receptors (RyR2)
• L-type Ca2+ channels (LCC)
• sarco/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a)
• reactive oxygen species

Acknowledgements

The authors thank Rodolfo Fernández, Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados-Instituto Politécnico Nacional, Ciudad de México, for excellent technical assistance. The authors thank Yolanda Contreras Vargas, Laboratorio de Nutrición Experimental, Instituto Nacional de Pediatría, for reference editing.

Disclosure statement

The authors declare no conflict of interest.

Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article [and/or] its Supplementary materials. Further details may be available on request from the corresponding author (KC)

Additional information

Funding

This work was supported by Consejo Nacional de Ciencia y Tecnologia (CONACyT) under Grant 151136 to NLGV and KC, and Institutional funds to protocol INP [11/048].