Journal
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
Volume 25, Issue 16, Pages 7642-7659Publisher
WILEY
DOI: 10.1111/jcmm.16601
Keywords
cardiac fibroblast; cardiac fibrosis; dapagliflozin; diabetic cardiomyopathy; endothelial-to-mesenchymal transition; oxidative stress; SGLT2 inhibitor
Categories
Funding
- National Natural Science Foundation of China [81670325, 81970368]
- Key Research and Development Project of Shandong Provence [2019GSF108124]
Ask authors/readers for more resources
The study found that the SGLT2 inhibitor dapagliflozin (DAPA) protects against diabetic cardiomyopathy (DCM) and myocardial fibrosis by suppressing fibroblast activation and endothelial-to-mesenchymal transition (EndMT) through the AMPK alpha-mediated inhibition of the TGF-beta/Smad signaling pathway.
Diabetic cardiomyopathy (DCM) is one of the leading causes of heart failure in patients with diabetes mellitus, with limited effective treatments. The cardioprotective effects of sodium-glucose cotransporter 2(SGLT2) inhibitors have been supported by amounts of clinical trials, which largely fills the gap. However, the underlying mechanism still needs to be further explored, especially in terms of its protection against cardiac fibrosis, a crucial pathophysiological process during the development of DCM. Besides, endothelial-to-mesenchymal transition (EndMT) has been reported to play a pivotal role in fibroblast multiplication and cardiac fibrosis. This study aimed to evaluate the effect of SGLT2 inhibitor dapagliflozin (DAPA) on DCM especially for cardiac fibrosis and explore the underlying mechanism. In vivo, the model of type 2 diabetic rats was built with high-fat feeding and streptozotocin injection. Untreated diabetic rats showed cardiac dysfunction, increased myocardial fibrosis and EndMT, which was attenuated after treatment with DAPA and metformin. In vitro, HUVECs and primary cardiac fibroblasts were treated with DAPA and exposed to high glucose (HG). HG-induced EndMT in HUVECs and collagen secretion of fibroblasts were markedly inhibited by DAPA. Up-regulation of TGF-beta/Smad signalling and activity inhibition of AMPK alpha were also reversed by DAPA treatment. Then, AMPK alpha siRNA and compound C abrogated the anti-EndMT effects of DAPA in HUVECs. From above all, our study implied that DAPA can protect against DCM and myocardial fibrosis through suppressing fibroblast activation and EndMT via AMPK alpha-mediated inhibition of TGF-beta/Smad signalling.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available