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SGLT1 Knockdown Attenuates Cardiac Fibroblast Activation in Diabetic Cardiac Fibrosis
Hui Lin1, Le Guan2, Liping Meng1
1Department of Cardiology, Shaoxing People's Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing, China.
Insights
Sodium-dependent glucose transporter 1 (SGLT1) drives cardiac fibroblast activation and fibrosis in diabetic cardiomyopathy. Inhibiting SGLT1 reduces fibrosis, offering a potential therapeutic target for diabetic heart disease.
Area of Science:
- Cardiovascular Biology
- Metabolic Disease Research
- Fibrosis Mechanisms
Background:
- Cardiac fibroblast activation is central to cardiac fibrosis in diabetic cardiomyopathy (DCM).
- Sodium-dependent glucose transporter 1 (SGLT1) inhibition shows promise in DCM, but its role in cardiac fibroblasts is unknown.
Purpose of the Study:
- To investigate the role of SGLT1 in cardiac fibroblast (CF) activation and its contribution to cardiac fibrosis in DCM.
Main Methods:
- Established a rat model of DCM and treated with SGLT1 siRNA (si-SGLT1).
- Conducted in vitro studies on high-glucose-treated CFs to assess proliferation, migration, and collagen synthesis.
- Analyzed protein expression and phosphorylation, including p38 MAPK and ERK1/2.
Main Results:
- SGLT1 was upregulated in diabetic hearts and high-glucose-treated CFs.
- High glucose increased CF proliferation, migration, collagen expression, and p38/ERK phosphorylation, which were reversed by si-SGLT1.
- SGLT1 silencing alleviated cardiac fibrosis but not cardiac hypertrophy in diabetic hearts.
Conclusions:
- SGLT1 plays a significant role in activating cardiac fibroblasts and promoting fibrosis in DCM.
- Targeting SGLT1 presents a novel therapeutic strategy for mitigating cardiac fibrosis in diabetic cardiomyopathy.
Abstract:
Background: Cardiac fibroblast (CF) activation is a hallmark feature of cardiac fibrosis in diabetic cardiomyopathy (DCM). Inhibition of the sodium-dependent glucose transporter 1 (SGLT1) attenuates cardiomyocyte apoptosis and delays the development of DCM. However, the role of SGLT1 in CF activation remains unclear. Methods: A rat model of DCM was established and treated with si-SGLT1 to examine cardiac fibrosis. In addition, in vitro experiments were conducted to verify the regulatory role of SGLT1 in proliferation and collagen secretion in high-glucose- (HG-) treated CFs. Results: SGLT1 was found to be upregulated in diabetic cardiac tissues and HG-induced CFs. HG stimulation resulted in increased proliferation and migration, increased the expression of transforming growth factor-β1 and collagen I and collagen III, and increased phosphorylation of p38 mitogen-activated protein kinase and extracellular signal-regulated kinase (ERK) 1/2. These trends in HG-treated CFs were significantly reversed by si-SGLT1. Moreover, the overexpression of SGLT1 promoted CF proliferation and collagen synthesis and increased phosphorylation of p38 mitogen-activated protein kinase and ERK1/2. SGLT1 silencing significantly alleviated cardiac fibrosis, but had no effect on cardiac hypertrophy in diabetic hearts. Conclusion: These findings provide new information on the role of SGLT1 in CF activation, suggesting a novel therapeutic strategy for the treatment of DCM fibrosis.
