Abstract
BackgroundCardiac 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.MethodsSprague–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.ResultsDAPA 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.ConclusionDAPA ameliorates Ang II-induced cardiac remodeling by regulating the TGF-β1/Smad signaling in a non-glucose-lowering dependent manner.
Highlights
Accentuated deposition of extracellular matrix (ECM) proteins contributed from cardiac fibroblasts (CFs) activation is a key feature of pathological myocardial remodeling involved in most etiologies of heart diseases, which increases myocardial stiffness and leads to the progression of heart failure [1]
Effects of DAPA on biochemical indicators and blood pressure (BP) in rats As shown in Table 1, there was no significant difference in the plasma glucose levels and insulin concentrations among the four groups throughout the study, indicating that Angiotensin II (Ang II)-infused rat model was free of diabetes
DAPA intervention showed a certain BP-lowering effect, but there was no significant difference between Ang II-infusion and Ang II + DAPA group (Table 2 and Additional file 1: Table S1)
Summary
Accentuated deposition of extracellular matrix (ECM) proteins contributed from cardiac fibroblasts (CFs) activation is a key feature of pathological myocardial remodeling involved in most etiologies of heart diseases, which increases myocardial stiffness and leads to the progression of heart failure [1]. Several mediators promote the development of cardiac fibrosis regardless of the underlying pathology and initiate factors. Among a wide range of fibrogenic signaling pathways, transforming growth factor-β1 (TGFβ1)/Smad is crucial for the induction and maintenance of CFs activation and collagen synthesis, which partially mediates Ang II-induced structural remodeling [6]. Studies have revealed that sodium–glucose cotransporter 2 inhibitors (SGLT2i), a new class of anti-diabetic drugs, could play a cardioprotective role beyond the glucose-lowering effect [8]. 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
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