Tohoku J. Exp. Med., 2023 August, 260(4)

LCZ696 Ameliorates Tachycardia-Induced Cardiac Calcium Dyshomeostasis in the SERCA2α-Dependent Pathway

Lan Liu,¹,² Sijia Sun,¹ Zhengkai Yang,¹ Shasha Zhu¹ and Cao Zou¹

¹Department of Cardiology, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, Jiangsu, China
²Department of Cardiology, Xishui Hospital Affiliated to Hubei University of Science and Technology, Huanggang, Hubei, China

The incidence, prevalence, and economic burden of heart failure have continued to increase worldwide. It remains unclear whether LCZ696 can ameliorate calcium reuptake in the sarcoplasmic reticulum via the sarcoplasmic endoplasmic reticulum calcium ion-ATPase 2α (SERCA2α)-dependent pathway during cardiac diastole. We investigated whether LCZ696 could ameliorate tachycardia-induced myocardial injury by modulating cardiac SERCA2α levels. A tachycardia-induced myocardial injury model was established by daily intraperitoneal administration of 60 mg/kg isoprenaline (ISO) for 2 weeks. LCZ696 was orally administered for the following 4 weeks. SERCA2α and calcium ion (Ca²⁺)-related protein expression was assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. For additional in vitro studies, HL-1 cardiomyocytes were used. A SERCA2α overexpression vector was constructed and transfected into HL-1 cells. The expression of SERCA2α and Ca²⁺-related proteins were also measured using qRT-PCR and western blotting. Our in vivo results demonstrated that myocardial injury was successfully induced by intraperitoneal administration of ISO. The expression of both SERCA2α- and Ca²⁺-related proteins was impaired. Oral administration of LCZ696 increased the expression of SERCA2α, alleviated Ca²⁺-related protein impairment and cardiac Ca²⁺ dyshomeostasis, and ameliorated myocardial injury. These results were compared with our in vitro findings. Ca²⁺-related proteins are affected by the overexpression of SERCA2α. LCZ696 improved tachycardia-induced myocardial injury by increasing SERCA2α expression, which reversed the development of heart failure in ISO-induced mice. These results provide new insights into how sustained LCZ696 treatment in heart failure improves cardiac function through intracellular Ca²⁺-regulatory mechanisms.

Key words —— calcium cycling; myocardial injury; sacubitril/valsartan (LCZ696); SERCA2α; tachycardia

© 2023 Tohoku University Medical Press

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Tohoku J. Exp. Med., 2023 August, 260(4), 315-327.

Correspondence: Cao Zou, Department of Cardiology, The First Affiliated Hospital of Soochow University, Soochow University, No. 188, Shizi Street, Suzhou, Jiangsu 215006, China.

e-mail: nkzc75@suda.edu.cn