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

Tomonari Kimura, Kazufumi Nakamura, Toru Miyoshi, Masashi Yoshida, Kaoru Akazawa, Yukihiro Saito, Satoshi Akagi, Yuko Ohno, Megumi Kondo, Daiji Miura, Jun Wada, Hiroshi Itoh

Research output: Contribution to journalArticle

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 β-hydroxybutyrate 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.

Original languageEnglish
Pages (from-to)728-735
Number of pages8
JournalInternational heart journal
Volume60
Issue number3
DOIs
Publication statusPublished - May 30 2019

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Inbred Dahl Rats
Cardiomegaly
High Fat Diet
Salts
Sodium-Glucose Transport Proteins
Blood Pressure
Ketone Bodies
Fibrosis
Ketones
Coenzyme A-Transferases
Hydroxybutyrate Dehydrogenase
Keto Acids
Natriuretic Peptides
3-Hydroxybutyric Acid
Collagen Type IV
Metabolome
6-((4-ethylphenyl)methyl)-3',4',5',6'-tetrahydro-6'-(hydroxymethyl)spiro(isobenzofuran-1(3H),2'-(2H)pyran)-3',4',5'-triol
Transforming Growth Factors
Cardiac Myocytes
Pharmaceutical Preparations

Keywords

  • Fibrosis
  • Hypertension
  • Ketone
  • SGLT2 inhibitor

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Inhibitory Effects of Tofogliflozin on Cardiac Hypertrophy in Dahl Salt-Sensitive and Salt-Resistant Rats Fed a High-Fat Diet. / Kimura, Tomonari; Nakamura, Kazufumi; Miyoshi, Toru; Yoshida, Masashi; Akazawa, Kaoru; Saito, Yukihiro; Akagi, Satoshi; Ohno, Yuko; Kondo, Megumi; Miura, Daiji; Wada, Jun; Itoh, Hiroshi.

In: International heart journal, Vol. 60, No. 3, 30.05.2019, p. 728-735.

Research output: Contribution to journalArticle

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AU - Akazawa, Kaoru

AU - Saito, Yukihiro

AU - Akagi, Satoshi

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