Dapagliflozin: A sodium-glucose cotransporter 2 inhibitor, attenuates angiotensin II-induced atrial fibrillation by regulating atrial electrical and structural remodeling.
Atrial fibrillation (AF), the most common arrhythmia, is characterized by atrial electrical and structural remodeling. Previous studies have found that sodium-glucose cotransporter 2 inhibitor (SGLT2i) can protect myocardium in a glucose independent mechanism. But the role of SGLT2i in regulating AF remains largely unknown. This study, we aimed to investigate the effect of Dapagliflozin (DAPA) in reducing AF susceptibility via inhibiting electrical and structural remodeling.
The mouse model was established by Angiotensin II (2000 ng/kg/min) infusion for 3 weeks, and an in vitro model was generated by stimulating HL-1 and primary mouse fibroblast with Ang II (1 μM) for 24 h. Programmed electrical stimulation, ECG and whole-cell patch clamp were used to detect DAPA effect on atrial electrical remodeling induced by Ang II. To observe DAPA effect on atrial structural remodeling induced by Ang II, we used echocardiographic, H&E and Masson staining to evaluate atrial dilation. To further explore the protective mechanism of DAPA, we adopt in silico molecular docking approaches to investigate the binding affinity of Ang II and CaMKII at Met-281 site. Western blot was to detect expression level of CaMKII, ox-CaMKII, Nav1.5, Kv4.3, Kv4.2, Kchip2, Kir2.1 and Cx40.
Ang II induced AF, atrial dilatation and fibrosis, led to atrial electrical and structural remodeling. However, these effects were markedly abrogated by DAPA treatment, a specific SGLT2i. Our observation of atrial electrical activity in mice revealed that DAPA could rescue the prolonged action potential duration (APD) and the abnormal currents of IK1, Ito and INaL triggered by Ang II infusion. DAPA could reduce the binding affinity of Ang II and CaMKII at Met-281 site, which indicated that DAPA may directly alleviate the activation of CaMKII caused by Ang II. DAPA could reduce the upregulation of ox-CaMKII caused by Ang II infusion in atrial tissues. Moreover, DAPA also ameliorated the aberrant expression levels of electrical activity related proteins (Nav1.5, Kv4.3, Kv4.2, Kchip2, Kir2.1 and Cx40) and fibrosis related signal pathways (TGF-β1, p-smad/smad) caused by Ang II. Furthermore, we confirmed that DAPA, as well as other SGLT2i (EMPA, CANA), could reverse these abnormalities caused by Ang II incubation in HL-1 cells and primary mouse fibroblasts, respectively.
Overall, our study identifies DAPA, a widely used SGLT2i, contributes to inhibiting Ang II-induced ox-CaMKII upregulation and electrical and structural remodeling to reduce AF susceptibility, suggesting that DAPA may be a potential therapy of treating AF.
Zhan G
，Wang X
，Wang X
，Li J
，Tang Y
，Bi H
，Yang X
，Xia Y
... -
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Dapagliflozin Attenuates Cardiac Remodeling in Mice Model of Cardiac Pressure Overload.
Dapagliflozin (DAPA) is an inhibitor of sodium-glucose cotransporter 2 prescribed for type 2 diabetes mellitus. DAPA plays a protective role against cardiovascular diseases. Nevertheless, the effect and mechanism of DAPA on pressure-overload-induced cardiac remodeling has not been determined.
We used a transverse aortic constriction (TAC) induced cardiac remodeling model to evaluate the effect of DAPA. Twenty-four C57BL/6J mice were divided into 3 groups: Sham, TAC, and TAC + DAPA groups (n = 8, each). DAPA was administered by gavage (1.0 mg/kg/day) for 4 weeks in the TAC + DAPA group, and then the myocardial hypertrophy, cardiac systolic function, myocardial fibrosis, and cardiomyocyte apoptosis were evaluated.
Mice in TAC group showed increased heart weight/body weight, left ventricular (LV) diameter, LV posterior wall thickness, and decreased LV ejection fraction and LV fractional shortening. The collagen volume fraction and perivascular collagen area/luminal area ratio were significantly greater in the TAC group; the TUNEL-positive cell number and PARP level were also increased. We found that DAPA treatment reduced myocardial hypertrophy, myocardial interstitial and perivascular fibrosis, and cardiomyocyte apoptosis. Furthermore, DAPA administration inhibited phosphorylation of P38 and JNK in TAC group. In addition, the inhibited phosphorylation of FoxO1 in the TAC mice was upregulated by DAPA administration.
DAPA administration had a cardioprotective effect by improving cardiac systolic function, inhibiting myocardial fibrosis and cardiomyocyte apoptosis in a TAC mouse model, indicating that it could serve as a new therapy to prevent pathological cardiac remodeling in nondiabetics.
Shi L
，Zhu D
，Wang S
，Jiang A
，Li F
... -
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The effects of liraglutide and dapagliflozin on cardiac function and structure in a multi-hit mouse model of heart failure with preserved ejection fraction.
Heart failure with preserved ejection fraction (HFpEF) is a multifactorial disease that constitutes several distinct phenotypes, including a common cardiometabolic phenotype with obesity and type 2 diabetes mellitus. Treatment options for HFpEF are limited, and development of novel therapeutics is hindered by the paucity of suitable preclinical HFpEF models that recapitulate the complexity of human HFpEF. Metabolic drugs, like glucagon-like peptide receptor agonist (GLP-1 RA) and sodium-glucose co-transporter 2 inhibitors (SGLT2i), have emerged as promising drugs to restore metabolic perturbations and may have value in the treatment of the cardiometabolic HFpEF phenotype. We aimed to develop a multifactorial HFpEF mouse model that closely resembles the cardiometabolic HFpEF phenotype, and evaluated the GLP-1 RA liraglutide (Lira) and the SGLT2i dapagliflozin (Dapa).
Aged (18-22 months old) female C57BL/6J mice were fed a standardized chow (CTRL) or high-fat diet (HFD) for 12 weeks. After 8 weeks HFD, angiotensin II (ANGII), was administered for 4 weeks via osmotic mini pumps. HFD + ANGII resulted in a cardiometabolic HFpEF phenotype, including obesity, impaired glucose handling, and metabolic dysregulation with inflammation. The multiple hit resulted in typical clinical HFpEF features, including cardiac hypertrophy and fibrosis with preserved fractional shortening but with impaired myocardial deformation, atrial enlargement, lung congestion, and elevated blood pressures. Treatment with Lira attenuated the cardiometabolic dysregulation and improved cardiac function, with reduced cardiac hypertrophy, less myocardial fibrosis, and attenuation of atrial weight, natriuretic peptide levels, and lung congestion. Dapa treatment improved glucose handling, but had mild effects on the HFpEF phenotype.
We developed a mouse model that recapitulates the human HFpEF disease, providing a novel opportunity to study disease pathogenesis and the development of enhanced therapeutic approaches. We furthermore show that attenuation of cardiometabolic dysregulation may represent a novel therapeutic target for the treatment of HFpEF.
Withaar C
，Meems LMG
，Markousis-Mavrogenis G
，Boogerd CJ
，Silljé HHW
，Schouten EM
，Dokter MM
，Voors AA
，Westenbrink BD
，Lam CSP
，de Boer RA
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