Inhibitory Effects of Tofogliflozin on Cardiac Hypertrophy in Dahl Salt-Sensitive and Salt-Resistant Rats Fed a High-Fat Diet

Abstract

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are drugs for diabetes and might prevent heart failure. In this study, we investigated the effects of tofogliflozin, an SGLT2 inhibitor, on cardiac hypertrophy and metabolism in hypertensive rats fed a high-fat diet. Dahl salt-sensitive (DS) rats, hypertensive model rats, and Dahl salt-resistant (DR) rats, non-hypertensive model rats, were fed a high-salt and high-fat diet containing tofogliflozin (0.005%) for 9 weeks to examine the effects of this drug on cardiac hypertrophy and metabolism. Tofogliflozin tended to suppress a rise of the systolic blood pressure, relative to the control, throughout the treatment period in both DR and DS rats, and significantly suppress a rise of the systolic blood pressure, relative to the control, at the 9th week in DS rats. Tofogliflozin reduced cardiac hypertrophy (heart weight/body weight) not only in DS rats but also in DR rats. Histological analysis showed that tofogliflozin significantly decreased cardiomyocyte hypertrophy and perivascular fibrosis in both DS and DR rats. Tofogliflozin significantly decreased the expression levels of genes related to cardiac hypertrophy (encoding for natriuretic peptides A and B and interleukin-6), and to cardiac fibrosis (encoding for transforming growth factor-β1 and collagen type IV), in DS rats. Recent studies have shown that hypertrophied and failing hearts shift to oxidizing ketone bodies as a significant fuel source. We also performed metabolome analysis for ventricular myocardial tissue. Tofogliflozin reduced 3-hydroxybutyrate, a ketone body, and significantly decreased the expression levels of βhydroxybutyrate dehydrogenase 1 and 3-oxoacid CoA-transferase, which are related to ketone oxidization. In conclusion, tofogliflozin ameliorated cardiac hypertrophy and fibrosis along with reduction of ketone usage in myocardial tissue.

Combination therapy with pemafibrate (K-877) and pitavastatin improves vascular endothelial dysfunction in dahl/salt-sensitive rats fed a high-salt and high-fat diet

“…Seven-week-old male Dahl salt-sensitive (DS) rats (n = 44) (Japan SLC, Shizuoka, Japan) were fed a normal diet (ND; 0.3% NaCl and 4.5% fat) (CE-2, CLEA Japan, Inc., Tokyo, Japan) or a high-salt and high-fat diet (HD; 8% NaCl and 29.4% fat) (CLEA Japan), as previously described [26], and they were treated with a vehicle (0.5% carboxy methyl cellulose and 0.5% methyl cellulose), pitavastatin (0.3 mg/kg/day) (Kowa Co., Ltd., Tokyo, Japan), pemafibrate (K-877) (0.5 mg/kg/day) (Kowa Co., Ltd.) or a combination of pitavastatin (0.3 mg/kg/day) and pemafibrate (K-877) (0.5 mg/kg/day) ( Fig. 1) by oral gavage for a period of 12 weeks (Fig.…”

Combination Therapy with Pemafibrate (K-877) and Pitavastatin Improves Vascular Endothelial Dysfunction in Dahl/Salt-sensitive Rats Fed a High-salt and High-fat Diet​

“…Seven-week-old male Dahl salt-sensitive (DS) rats (n = 44) (Japan SLC, Shizuoka, Japan) were fed a normal diet (ND; 0.3% NaCl and 4.5% fat) (CE-2, CLEA Japan, Inc., Tokyo, Japan) or a high-salt and highfat diet (HD; 8% NaCl and 29.4% fat) (CLEA Japan), as previously described [26], and they were treated with a vehicle (0.5% carboxy methyl cellulose and 0.5% methyl cellulose), pitavastatin (0.3 mg/kg/day) (Kowa Co., Ltd., Tokyo, Japan), pema brate (K-877) (0.5 mg/kg/day) (Kowa Co., Ltd.) or a combination of pitavastatin (0.3 mg/kg/day) and pema brate (K-877) (0.5 mg/kg/day) ( Figure 1) by oral gavage for a period of 12 weeks (Figure 1). Body weight was measured once a week for a period of 12 weeks.…”

Mechanisms and Perspectives of Sodium-Glucose Co-transporter 2 Inhibitors in Heart Failure

“…In a multi-hit mouse model of HFpEF, dapagliflozin also improved cardiac function and tissue fibrosis (123). Tofogliflozin, another SGLT2 inhibitor, ameliorated cardiac hypertrophy and fibrosis in dahl saltsensitive and salt-resistant rats fed a high-fat diet (124). These experimental studies suggest that SGLT2 inhibitors may be beneficial for patients with HFpEF.…”