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. 2017 Jan 13;16(1):9.
doi: 10.1186/s12933-016-0489-z.

Sodium Glucose Transporter 2 (SGLT2) Inhibition With Empagliflozin Improves Cardiac Diastolic Function in a Female Rodent Model of Diabetes

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Free PMC article

Sodium Glucose Transporter 2 (SGLT2) Inhibition With Empagliflozin Improves Cardiac Diastolic Function in a Female Rodent Model of Diabetes

Javad Habibi et al. Cardiovasc Diabetol. .
Free PMC article

Abstract

Obese and diabetic individuals are at increased risk for impairments in diastolic relaxation and heart failure with preserved ejection fraction. The impairments in diastolic relaxation are especially pronounced in obese and diabetic women and predict future cardiovascular disease (CVD) events in this population. Recent clinical data suggest sodium glucose transporter-2 (SGLT2) inhibition reduces CVD events in diabetic individuals, but the mechanisms of this CVD protection are unknown. To determine whether targeting SGLT2 improves diastolic relaxation, we utilized empagliflozin (EMPA) in female db/db mice. Eleven week old female db/db mice were fed normal mouse chow, with or without EMPA, for 5 weeks. Blood pressure (BP), HbA1c and fasting glucose were significantly increased in untreated db/db mice (DbC) (P < 0.01). EMPA treatment (DbE) improved glycemic indices (P < 0.05), but not BP (P > 0.05). At baseline, DbC and DbE had already established impaired diastolic relaxation as indicated by impaired septal wall motion (>tissue Doppler derived E'/A' ratio) and increased left ventricular (LV) filling pressure (<E/E' ratio). Although these abnormalities persisted throughout the study period in DbC, diastolic function improved with EMPA treatment. In DbC, myocardial fibrosis was accompanied by increased expression of profibrotic/prohypertrophic proteins, serum/glucocorticoid regulated kinase 1 (SGK1) and the epithelial sodium channel (ENaC), and the development of these abnormalities were reduced with EMPA. DbC exhibited eccentric LV hypertrophy that was slightly improved by EMPA, indicated by a reduction in cardiomyocyte cross sectional area. In summary, EMPA improved glycemic indices along with diastolic relaxation, as well as SGK1/ENaC profibrosis signaling and associated interstitial fibrosis, all of which occurred in the absence of any changes in BP.

Keywords: Diastolic function; Empagliflozin; SGLT2 inhibitor.

Figures

Fig. 1
Fig. 1
Empagliflozin improves dysglycemia in db/db mice. Db/db mice have elevated fasting glucose and HbA1c levels prior to the start of treatment. During the 5 week study period, dysglycemia was sustained in untreated db/db mice (DbC); however both a fasting glucose and b HbA1c were reduced in db/db treated with empagliflozin (DbE) by the end of the study. At the end of the study, DbE had increased c serum insulin concentrations and d pancreas mass e compared to CKC and DbC. e Compared to CkC, urine glucose excretion (UGE) was elevated in both db/db groups of mice, but UGE was twofold higher in DbE compared to DbC. *P < 0.05 compared to CkC at the same time point; P < 0.05 compared to DbC at the same time point
Fig. 2
Fig. 2
Mean ambulatory systolic and diastolic blood pressures were recorded at weekly intervals during the light a and dark b cycles. Compared to CkC, both DbC and DbE exhibited a mild elevation in blood pressure (P < 0.05), especially during the light cycle and tended to have impaired blood pressure dipping (c), neither of which was affected by empagliflozin treatment. *P < 0.05DbC vs CkC and §P < 0.05 DbE vs CkC
Fig. 3
Fig. 3
Echocardiographic assessment of diastolic function. Cardiac function was evaluated in 11 week old mice prior to treatment (Pre) and again at 15 weeks of age at the end of treatment. Bar graphs show significant improvements in diastolic parameters in DbE compared to DbC including the a Tissue Doppler derived E′/A′ ratio indicating improved septal wall motion and b E/E′ ratio indicating improved LV filling pressure. *P < 0.05 compared to CKC at the same time point; P < 0.05 compared to DbC at the same time point
Fig. 4
Fig. 4
Myocardial remodeling, but not oxidative stress is improved with empagliflozin. a WGA staining for determination of myocyte cross sectional area (CSA), magnification ×40, b Picrosirius red staining for determination of interstitial fibrosis. Magnification ×5, inset ×40 and c 3-nitrotyrosine immunostaining for determination of oxidative stress. Magnification ×40, inset ×40. *P < 0.05 vs CkC and P < 0.05 vs DbC. AGSI average grey scale intensities. All scale bars 50 μm
Fig. 5
Fig. 5
Five weeks of empagliflozin treatment reduces the profibrotic protein expression levels of a, b ENaC and c SGK1. AGSI average grey scale intensities, AU arbitrary units *P < 0.05 vs CkC; P < 0.05 vs DbC. Scale bars 50 μm
Fig. 6
Fig. 6
Empagliflozin reduces myocardial profibrotic signaling. Five weeks of empagliflozin treatment reduces the profibrotic proein expression levels of a, b ENaC and c SGK1. AGSI average grey scale intensities, AU arbitrary units *P < 0.05 vs CkC; P < 0.05 vs DbC. Scale bars 50 µm
Fig. 7
Fig. 7
Mitochondrial expansion and sarcomere disorganization in DbC is improved by empagliflozin treatment. a Illustrates the normal appearance of the inter myofibrillar (IMF) mitochondria (Mt) in the myocardium of CkC. Note the orderly row of sarcomeres (S) alternating with a row of IMF-Mt. Inset a shows normal cristae structure. b Depicts the marked IMF-Mt expansion with attenuation of the Mt matrix electron density, loss of Mt cristae (inset b), fusion of Mt cristae and Mt fragmentation in the diabetic DbC models. Also note the disorganized appearance of the sarcomeres. c Demonstrates that empagliflozin protects the cardiomyocyte from IMF-Mt expansion, decreased IMF-Mt matrix electron density, IMF-Mt cristae fragmentation (inset c), fusion of cristae and loss and sarcomere disorganization. Magnification ×2000; bar 1 µm in ac. Insets ac depict Mt cristae structure. Magnification ×4000; bar 0.5 µm. df represent CkC, DbC and DbE, respectively, at lower magnifications ×800; bar 2 µm

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