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 ... -  《-》

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

Zhang Y ，Lin X ，Chu Y ，Chen X ，Du H ，Zhang H ，Xu C ，Xie H ，Ruan Q ，Lin J ，Liu J ，Zeng J ，Ma K ，Chai D ... -  《Cardiovascular Diabetology》

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 ... -  《-》

Direct Cardiac Actions of the Sodium Glucose Co-Transporter 2 Inhibitor Empagliflozin Improve Myocardial Oxidative Phosphorylation and Attenuate Pressure-Overload Heart Failure.

Li X ，Lu Q ，Qiu Y ，do Carmo JM ，Wang Z ，da Silva AA ，Mouton A ，Omoto ACM ，Hall ME ，Li J ，Hall JE ... -  《Journal of the American Heart Association》

SGLT-2 Inhibition with Dapagliflozin Reduces the Activation of the Nlrp3/ASC Inflammasome and Attenuates the Development of Diabetic Cardiomyopathy in Mice with Type 2 Diabetes. Further Augmentation of the Effects with Saxagliptin, a DPP4 Inhibitor.

Ye Y ，Bajaj M ，Yang HC ，Perez-Polo JR ，Birnbaum Y ... -  《-》