Fructose aggravates copper-deficiency-induced cardiac remodeling by inhibiting SERCA2a

Author:

Xu Yi1,Xu Qiuxia1,Zheng Zhirui1,Jiang Xin1,Shi Yuansen1,Huang Yipu1,Liu Yun1ORCID

Affiliation:

1. Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University , Guangzhou 511436 , PR China

Abstract

Abstract Objectives Accumulating evidence demonstrates that copper deficiency (CuD) is a risk factor for cardiovascular diseases, besides, fructose has been strongly linked to the development of cardiovascular diseases. However, how CuD or fructose causes cardiovascular diseases is not clearly delineated. The present study aims to investigate the mechanism of CuD or fructose on cardiac remodeling. Methods We established a model of CuD- or fructose-induced cardiac hypertrophy in 3-week-old male Sprague–Dawley (SD) rats by CuD diet supplemented with or without 30% fructose for 4 weeks. In vitro study was performed by treating cardiomyocytes with tetrathiomolydbate (TM) and fructose. Echocardiography, histology analysis, immunofluorescence, western blotting, and qPCR were performed. Key findings Our findings revealed that CuD caused noticeable cardiac hypertrophy either in the presence or absence of fructose supplement. Fructose exacerbated CuD-induced cardiac remodeling and intramyocardial lipid accumulation. Furthermore, we presented that the inhibition of autophagic flux caused by Ca2+ disturbance is the key mechanism by which CuD- or fructose-induced cardiac remodeling. The reduced expression of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) in cardiomyocytes accounts for the elevated cytoplasmic Ca2+ concentration. Conclusions Collectively, our study suggested that fructose aggravated CuD-induced cardiac remodeling through the blockade of autophagic flux via SERCA2a decreasing-induced Ca2+ imbalance.

Funder

High-level University Construction Fund

Guangzhou Medical University

Publisher

Oxford University Press (OUP)

Subject

Pharmaceutical Science,Pharmacology

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