Journal Article

Dapagliflozin: a sodium–glucose cotransporter 2 inhibitor, attenuates angiotensin II-induced cardiac fibrotic remodeling by regulating TGFβ1/Smad signaling

Zeng, Jinzhang, Chu, Yong, Xu, Changsheng, Chen, Xiaoming, Liu, Jie, Ma, Ke, Lin, Jinxiu, Chai, Dajun, Zhang, Yuze, Ruan, Qinyun, Du, Heng, Xie, Hong, Zhang, Hailin, Lin, Xiaoyan

2021

Overview

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.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Angiology / Angiotensin / Angiotensin II / Animals / Antidiabetics / Antifibrotic Agents - pharmacology / Benzhydryl Compounds - pharmacology / Blood pressure / Body weight / Cardiac fibrotic remodeling / Cardiology / Cardiomyocytes / Cells, Cultured / Chronic fatigue syndrome / Collagen / Congestive heart failure / Dapagliflozin / Diabetes / Diabetes mellitus (non-insulin dependent) / Disease Models, Animal / Echocardiography / Ejection fraction / Fibroblasts / Fibroblasts - drug effects / Fibroblasts - metabolism / Fibroblasts - pathology / Fibrosis / Glucose / Glucosides - pharmacology / Heart failure / Hypertrophy / Hypertrophy, Left Ventricular - chemically induced / Hypertrophy, Left Ventricular - metabolism / Hypertrophy, Left Ventricular - pathology / Hypertrophy, Left Ventricular - prevention & control / Kinases / Laboratory animals / Male / Medicine / Medicine & Public Health / Myocardium - metabolism / Myocardium - pathology / Original Investigation / Peptides / Proteins / Rats / Rats, Sprague-Dawley / Risk factors / Signal Transduction / Smad protein / Smad Proteins - metabolism / Smooth muscle / Sodium-glucose cotransporter / Sodium-Glucose Transporter 2 Inhibitors - pharmacology / Sodium–glucose cotransporter 2 inhibitors / Software / Structure-function relationships / TGFβ1/Smad signaling / Transforming Growth Factor beta1 - metabolism / Transforming growth factor-b1 / Velocity / Ventricle / Ventricular Dysfunction, Left - chemically induced / Ventricular Dysfunction, Left - metabolism / Ventricular Dysfunction, Left - pathology / Ventricular Dysfunction, Left - prevention & control / Ventricular Function, Left - drug effects / Ventricular Remodeling - drug effects