High fructose levels inhibit the proliferation of cardiomyocytes via the Notch1 signaling pathway

Fei Ma; Xiji Qin; Junjie Yang; Xin Zhou; Jianyuan Zhao; Ke Cai; Rui Zhao; Yan Shi; Kun Sun

doi:10.1016/j.cellsig.2025.111600

High fructose levels inhibit the proliferation of cardiomyocytes via the Notch1 signaling pathway

Cell Signal. 2025 Jan 8:111600. doi: 10.1016/j.cellsig.2025.111600. Online ahead of print.

Authors

Fei Ma¹, Xiji Qin², Junjie Yang², Xin Zhou¹, Jianyuan Zhao³, Ke Cai³, Rui Zhao³, Yan Shi⁴, Kun Sun⁵

Affiliations

¹ Department of Pediatric Cardiology, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou 325038, Zhejiang, China.
² Department of Pediatric Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China.
³ Institute for Development and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children's Environment Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200090, China.
⁴ Institute for Development and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children's Environment Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200090, China; Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Hefei 230000, Anhui, China.
⁵ Department of Pediatric Cardiology, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou 325038, Zhejiang, China; Department of Pediatric Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China. Electronic address: sunkun@xinhuamed.com.cn.

PMID: 39793743
DOI: 10.1016/j.cellsig.2025.111600

Abstract

Fructose, as a natural and simple sugar, is not significantly harmful to the human body when consumed in moderation and can provide energy for the body. High-fructose diets have been linked to an increased risk of a range of metabolic disorders, including hypertriglyceridemia, hypertension, and diabetes mellitus. These conditions are known to be associated with an elevated risk of developing cardiometabolic diseases. Cardiomyocytes in mammals possess the capacity to proliferate from the moment of their birth. However, this capacity diminishes over time, and cardiac growth is ultimately achieved through cardiomyocyte (CM) hypertrophy. Prior studies have demonstrated that fructose metabolism is enhanced in the heart during pathological hypertrophy [1]. The consumption of foods containing high levels of fructose has been linked to an increase in the size of cardiomyocytes, which can lead to damage to the heart. The impact of high fructose on cardiomyocytes at the point of their initial capacity for proliferation has not been previously documented. In this experiment, our purpose was to explore the impact of high fructose in cardiomyocyte proliferation. To establish an apical resection model in neonatal mice, neonatal ICR mice were randomly divided into a sham-operated group (Sham + PBS), a sham-operated combined high-fructose group (Sham + fructose), an apical resection alone group (AR + PBS) and an apical resection combined with a high-fructose group (AR + fructose). Next, echocardiography was employed to assess the cardiac function of all mice. Masson staining was carried out to analyze cardiac fibrosis. Immunostaining was performed by extracting primary rat cardiomyocytes after the high-fructose intervention to see if proliferation-related markers (Ki67, PH3, Aurora-B) changed, qRT-PCR and immunofluorescence were used to determine changes in the expression profile of Notch1 in the neonatal heart. The results suggest that high fructose could inhibit cardiomyocyte proliferation in vivo and in vitro, The possible mechanism is that high fructose levels inhibit cardiomyocyte proliferation through suppression of Notch1 signaling pathway. In conclusion, high fructose levels inhibit the proliferation of cardiomyocytes via the Notch1 signaling pathway.

Keywords: Cardiomyocyte proliferation; Fructose; Notch1 signaling pathway.