Eicosapentaenoic Acid Rescues Cav1.2-L-Type Ca2+ Channel Decline Caused by Saturated Fatty Acids via Both Free Fatty Acid Receptor 4-Dependent and -Independent Pathways in Cardiomyocytes

Morishima, Masaki; Wang, Pu; Horii, Kosuke; Horikawa, Kazuki; Ono, Katsushige

doi:10.3390/ijms25147570

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Eicosapentaenoic Acid Rescues Cav1.2-L-Type Ca²⁺ Channel Decline Caused by Saturated Fatty Acids via Both Free Fatty Acid Receptor 4-Dependent and -Independent Pathways in Cardiomyocytes

by

Masaki Morishima

^1,2,*,

Pu Wang

³,

Kosuke Horii

²,

Kazuki Horikawa

⁴

and

Katsushige Ono

^3,5,*

¹

Department of Food Science and Nutrition, Faculty of Agriculture, Kindai University, Nara 6318505, Japan

²

Department of Applied Biological Chemistry, Graduate School of Agriculture, Kindai University, Nara 6318505, Japan

³

Department of Pathophysiology, Oita University School of Medicine, Yufu 8795593, Japan

⁴

Department of Optical Imaging, Advanced Research Promotion Center, Tokushima University, Tokushima 7708503, Japan

⁵

Oita Shimogori Hospital, Oita 8700926, Japan

^*

Authors to whom correspondence should be addressed.

Int. J. Mol. Sci. 2024, 25(14), 7570; https://doi.org/10.3390/ijms25147570

Submission received: 29 April 2024 / Revised: 3 July 2024 / Accepted: 8 July 2024 / Published: 10 July 2024

(This article belongs to the Special Issue Cardiac Arrhythmia: Molecular Mechanisms and Therapeutic Strategies)

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Abstract

Dietary intake of omega-3 polyunsaturated fatty acids (eicosapentaenoic acid, EPA) exerts antiarrhythmic effects, although the mechanisms are poorly understood. Here, we investigated the possible beneficial actions of EPA on saturated fatty acid-induced changes in the L-type Ca²⁺ channel in cardiomyocytes. Cardiomyocytes were cultured with an oleic acid/palmitic acid mixture (OAPA) in the presence or absence of EPA. Beating rate reduction in cardiomyocytes caused by OAPA were reversed by EPA. EPA also retrieved a reduction in Cav1.2 L-type Ca²⁺ current, mRNA, and protein caused by OAPA. Immunocytochemical analysis revealed a distinct downregulation of the Cav1.2 channel caused by OAPA with a concomitant decrease in the phosphorylated component of a transcription factor adenosine-3′,5′-cyclic monophosphate (cAMP) response element binding protein (CREB) in the nucleus, which were rescued by EPA. A free fatty acid receptor 4 (FFAR4) agonist TUG-891 reversed expression of Cav1.2 and CREB mRNA caused by OAPA, whereas an FFAR4 antagonist AH-7614 abolished the effects of EPA. Excessive reactive oxygen species (ROS) accumulation caused by OAPA decreased Cav1.2 and CREB mRNA expressions, which was reversed by an ROS scavenger. Our data suggest that EPA rescues cellular Cav1.2-Ca²⁺ channel decline caused by OAPA lipotoxicity and oxidative stresses via both free fatty acid receptor 4-dependent and -independent pathways.

Keywords: eicosapentaenoic acid; oleic acid; palmitic acid; omega-3 polyunsaturated fatty acid; PUFA; FFAR4; CREB; Cav1.2; L-type Ca²⁺ channel

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MDPI and ACS Style

Morishima, M.; Wang, P.; Horii, K.; Horikawa, K.; Ono, K. Eicosapentaenoic Acid Rescues Cav1.2-L-Type Ca²⁺ Channel Decline Caused by Saturated Fatty Acids via Both Free Fatty Acid Receptor 4-Dependent and -Independent Pathways in Cardiomyocytes. Int. J. Mol. Sci. 2024, 25, 7570. https://doi.org/10.3390/ijms25147570

AMA Style

Morishima M, Wang P, Horii K, Horikawa K, Ono K. Eicosapentaenoic Acid Rescues Cav1.2-L-Type Ca²⁺ Channel Decline Caused by Saturated Fatty Acids via Both Free Fatty Acid Receptor 4-Dependent and -Independent Pathways in Cardiomyocytes. International Journal of Molecular Sciences. 2024; 25(14):7570. https://doi.org/10.3390/ijms25147570

Chicago/Turabian Style

Morishima, Masaki, Pu Wang, Kosuke Horii, Kazuki Horikawa, and Katsushige Ono. 2024. "Eicosapentaenoic Acid Rescues Cav1.2-L-Type Ca²⁺ Channel Decline Caused by Saturated Fatty Acids via Both Free Fatty Acid Receptor 4-Dependent and -Independent Pathways in Cardiomyocytes" International Journal of Molecular Sciences 25, no. 14: 7570. https://doi.org/10.3390/ijms25147570

APA Style

Morishima, M., Wang, P., Horii, K., Horikawa, K., & Ono, K. (2024). Eicosapentaenoic Acid Rescues Cav1.2-L-Type Ca²⁺ Channel Decline Caused by Saturated Fatty Acids via Both Free Fatty Acid Receptor 4-Dependent and -Independent Pathways in Cardiomyocytes. International Journal of Molecular Sciences, 25(14), 7570. https://doi.org/10.3390/ijms25147570

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Eicosapentaenoic Acid Rescues Cav1.2-L-Type Ca²⁺ Channel Decline Caused by Saturated Fatty Acids via Both Free Fatty Acid Receptor 4-Dependent and -Independent Pathways in Cardiomyocytes

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