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Published on: May 26, 2023
Secreted frizzled-related protein 2 ameliorates diabetic cardiomyopathy by activating mitophagy
Haoxiao Zheng1, Weiwen Li2, Guolin Huang2
1Department of Cardiology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), NO. 1 Jiazi Road, Lunjiao, Shunde District, Foshan City, Guangdong 528308, China.
Objectives:
Secreted frizzled-related protein 2 (SFRP2), a novel adipokine that used to be considered an inhibitor of the canonical Wnt pathway, may play a protective role in metabolic disorders. However, its effect on diabetic cardiomyopathy was still unclear. Accumulating evidence indicates that mitophagy can protect cardiac function in the diabetic heart. The present study aimed to explore the roles of SFRP2 on diabetic cardiomyopathy, focusing on the effects and mechanisms for regulating mitophagy.
Methods:
Wild-type H9c2 cells, Sfrp2 overexpression and knockdown H9c2 cells were exposed to a glucolipotoxic milieu. Reactive oxygen species (ROS) production, cell viability, apoptosis, mitophagy and lysosomal activity were detected. The interaction of SFRP2 with frizzled 5 (FZD5), and its effect on expression and intracellular localization of transcription factor EB (TFEB) and β-catenin were also explored. Diabetic rats and Sfrp2 overexpression diabetic rats were constructed to further document the findings from the in vitro study.
Results:
The expression of SFRP2 was low and mitophagy was inhibited in H9c2 cells in a glucolipotoxic milieu. Sfrp2 overexpression activated mitophagy and reduced H9c2 cells injury, whereas Sfrp2 deficiency inhibited mitophagy and worsened this injury. Consistent with the in vitro findings, Sfrp2 overexpression ameliorated the impairment in cardiac function of diabetic rats by activating mitophagy. Sfrp2 overexpression upregulated the expression of calcineurin and TFEB, but did not affect β-catenin in vitro and in vivo. The calcineurin inhibitor tacrolimus can inhibit mitophagy and worsen cell injury in Sfrp2 overexpression H9c2 cells. Furthermore, we found that FZD5 is required for the SFRP2-induced activation of the calcineurin/TFEB pathway and interacts with SFRP2 in H9c2 cells. Transfection with small interfering RNA targeting FZD5 opposed the effects of Sfrp2 overexpression on mitophagy and cell survival in a glucolipotoxic environment.
Conclusions:
SFRP2 can protect the diabetic heart by interacting with FZD5 and activating the calcineurin/TFEB pathway to upregulate mitophagy in H9c2 cells.
Insights
Secreted frizzled-related protein 2 (SFRP2) protects against diabetic cardiomyopathy by enhancing mitophagy. This adipokine interacts with Frizzled 5 (FZD5) to activate the calcineurin/TFEB pathway, improving cardiac function in diabetes.
Area of Science:
- Cardiovascular Research
- Metabolic Disorders
- Cellular Biology
Background:
- Secreted frizzled-related protein 2 (SFRP2) is a novel adipokine with potential protective roles in metabolic disorders.
- The specific impact of SFRP2 on diabetic cardiomyopathy and its underlying mechanisms, particularly mitophagy, remains largely unexplored.
- Mitophagy is recognized for its cardioprotective effects in diabetic conditions.
Purpose of the Study:
- To investigate the role of SFRP2 in diabetic cardiomyopathy.
- To elucidate the mechanisms by which SFRP2 influences mitophagy in the context of diabetes.
- To determine the therapeutic potential of SFRP2 in mitigating cardiac dysfunction.
Main Methods:
- In vitro studies using H9c2 cells exposed to glucolipotoxicity, with SFRP2 overexpression or knockdown.
- Assessment of reactive oxygen species (ROS), cell viability, apoptosis, mitophagy, and lysosomal activity.
- In vivo studies using diabetic rat models with and without SFRP2 overexpression, examining cardiac function and molecular pathways.
Main Results:
- SFRP2 expression was reduced, and mitophagy inhibited in glucolipotoxic conditions.
- SFRP2 overexpression enhanced mitophagy and reduced cell injury, while SFRP2 deficiency exacerbated injury.
- SFRP2 overexpression improved cardiac function in diabetic rats by activating mitophagy, upregulating calcineurin and TFEB, and interacting with FZD5.
Conclusions:
- SFRP2 demonstrates a protective effect against diabetic cardiomyopathy.
- SFRP2 activates the calcineurin/TFEB pathway via interaction with FZD5, leading to enhanced mitophagy.
- SFRP2 represents a potential therapeutic target for managing diabetic heart disease.
