Key result
Dapagliflozin pretreatment significantly ameliorated left ventricular dysfunction, myocardial hypertrophy, and fibrosis in Angiotensin II-infused rats by inhibiting TGF-β1/Smad signaling.
Why the study?
SGLT2 inhibitors reduce heart failure hospitalizations potentially via glucose-independent mechanisms, but the underlying mechanisms and efficacy of dapagliflozin in reducing cardiac remodeling remain largely unknown.
Does dapagliflozin attenuate angiotensin II-induced cardiac fibrotic remodeling in a rat model?
Does dapagliflozin attenuate angiotensin II-induced cardiac fibrotic remodeling in a rat model?
Dapagliflozin attenuates angiotensin II-induced cardiac remodeling and fibrosis by regulating TGF-β1/Smad signaling independently of its glucose-lowering effects.
Preclinical anti-remodeling signal warrants no practice change; leaves open human trials of TGF-β1/Smad targeting by SGLT2i.
BACKGROUND: Cardiac remodeling is one of the major risk factors for heart failure. In patients with type 2 diabetes, sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of the first hospitalization for heart failure, possibly through glucose-independent mechanisms in part, but the underlying mechanisms remain largely unknown. This study aimed to shed light on the efficacy of dapagliflozin in reducing cardiac remodeling and potential mechanisms. METHODS: Sprague-Dawley (SD) rats, induced by chronic infusion of Angiotensin II (Ang II) at a dose of 520 ng/kg per minute for 4 weeks with ALZET® mini-osmotic pumps, were treated with either SGLT2 inhibitor dapagliflozin (DAPA) or vehicle alone. Echocardiography was performed to determine cardiac structure and function. Cardiac fibroblasts (CFs) were treated with Ang II (1 μM) with or without the indicated concentration (0.5, 1, 10 μM) of DAPA. The protein levels of collagen and TGF-β1/Smad signaling were measured along with body weight, and blood biochemical indexes. RESULTS: DAPA pretreatment resulted in the amelioration of left ventricular dysfunction in Ang II-infused SD rats without affecting blood glucose and blood pressure. Myocardial hypertrophy, fibrosis and increased collagen synthesis caused by Ang II infusion were significantly inhibited by DAPA pretreatment. In vitro, DAPA inhibit the Ang II-induced collagen production of CFs. Immunoblot with heart tissue homogenates from chronic Ang II-infused rats revealed that DAPA inhibited the activation of TGF-β1/Smads signaling. CONCLUSION: DAPA ameliorates Ang II-induced cardiac remodeling by regulating the TGF-β1/Smad signaling in a non-glucose-lowering dependent manner.
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Zhang et al. (2021) studied Angiotensin II-induced cardiac remodeling (n=24). Dapagliflozin vs. Vehicle (0.9% sterile saline) was evaluated on Cardiac remodeling and left ventricular dysfunction. Dapagliflozin pretreatment significantly ameliorated left ventricular dysfunction, myocardial hypertrophy, and fibrosis in Angiotensin II-infused rats by inhibiting TGF-β1/Smad signaling.
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