Dapagliflozin alleviates cardiac fibrosis through suppressing EndMT and fibroblast activation via AMPKα/TGF‐β/Smad signalling in type 2 diabetic rats

Abstract

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‐β/Smad signalling and activity inhibition of AMPKα were also reversed by DAPA treatment. Then, AMPKα 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 AMPKα‐mediated inhibition of TGF‐β/Smad signalling.

Mesenchymal Stem Cell Therapy in Diabetic Cardiomyopathy

“…The transcription level of EndMT markers (snail 1, snail 2, twist 1 and twist 2) was also elevated in diabetic rat hearts. Importantly, inhibition of the TGF-β/Smad pathway can be achieved by dapagliflozin and metformin through AMPKα activation, with the suppression of cardiac fibroblast activity [ 59 ].…”

The Active Compounds and Therapeutic Target of Tripterygium wilfordii Hook. f. in Attenuating Proteinuria in Diabetic Nephropathy: A Review

“…TGF-β1/Smad signaling pathway plays a critical role in prolonged glomerulosclerosis, which is an important determinant during the progression in DN ( 86 ). Bone morphogenetic protein-7 (BMP-7) is a critical developmental and differentiation factor in the kidney, which can inhibit TGF-β signaling to ameliorate renal inflammation, apoptosis, and fibrosis after kidney injury ( 87 , 88 ).…”

“…It is currently believed that renal fibrosis develops in response to ECM accumulation due to epithelialmesenchymal transition (EMT), TGF-β signaling, oxidative stress and proteinuria (84,85). TGF-β1/Smad signaling pathway plays a critical role in prolonged glomerulosclerosis, which is an important determinant during the progression in DN (86). Bone morphogenetic protein-7 (BMP-7) is a critical developmental and differentiation factor in the kidney, which can inhibit TGF-β signaling to ameliorate renal inflammation, apoptosis, and fibrosis after kidney injury (87,88).…”

Inflammation and Oxidative Stress in Diabetic Kidney Disease: The Targets for SGLT2 Inhibitors and GLP-1 Receptor Agonists

“…Moreover, glycolysis supports fibrosis by fueling myofibroblasts with energy and EMT induction. It has been shown recently that restoration of SIRT 3 level by SGLT2 inhibitors leads to suppression of aberrant glycolysis [ 78 ]. SGLT2i therefore are expected to reduce hypoxic stress, and it may be hypothesized that on a long-term basis it would lead to prevention of progression of DKD ( Figure 1 ).…”

“…As in the in vivo experiment, all above features of fibroblast activation and EndMT of HUVEC were ameliorated by dapagliflozin and metformin. Both drugs were shown to restore significantly diminished AMPK activity in high glucose medium; using siRNA or compound C to inactivate AMPK diminished all beneficial effects exerted by dapagliflozin [ 78 ].…”