An Effective Sodium-Dependent Glucose Transporter 2 Inhibition, Canagliflozin, Prevents Development of Hypertensive Heart Failure in Dahl Salt-Sensitive Rats

Lili He; Sai Ma; Qingjuan Zuo; Guorui Zhang; Zhongli Wang; Tingting Zhang; Jianlong Zhai; Yifang Guo

doi:10.3389/fphar.2022.856386

An Effective Sodium-Dependent Glucose Transporter 2 Inhibition, Canagliflozin, Prevents Development of Hypertensive Heart Failure in Dahl Salt-Sensitive Rats

Front Pharmacol. 2022 Mar 9:13:856386. doi: 10.3389/fphar.2022.856386. eCollection 2022.

Authors

Lili He^{1

2}, Sai Ma^{1

3}, Qingjuan Zuo², Guorui Zhang⁴, Zhongli Wang⁵, Tingting Zhang², Jianlong Zhai⁶, Yifang Guo^{1

2}

Affiliations

¹ Department of Internal Medicine, Hebei Medical University, Shijiazhuang, China.
² Department of Geriatric Cardiology, Hebei General Hospital, Shijiazhuang, China.
³ Department of Internal Medicine, Hebei General Hospital, Shijiazhuang, China.
⁴ Department of Cardiology, The Third Hospital of Shijiazhuang City Affiliated to Hebei Medical University, Shijiazhuang, China.
⁵ Department of Physical Examination Center, Hebei General Hospital, Shijiazhuang, China.
⁶ Department of Cardiology, Hebei General Hospital, Shijiazhuang, China.

Abstract

Background: The aim of the study was to investigate the protective effect of canagliflozin (CANA) on myocardial metabolism and heart under stress overload and to further explore its possible molecular mechanism. Methods: High-salt diet was used to induce heart failure with preserved ejection fraction (HFpEF), and then, the physical and physiological indicators were measured. The cardiac function was evaluated by echocardiography and related indicators. Masson trichrome staining, wheat germ agglutinin, and immunohistochemical staining were conducted for histology analysis. Meanwhile, oxidative stress and cardiac ATP production were also determined. PCR and Western blotting were used for quantitative detection of related genes and proteins. Comprehensive metabolomics and proteomics were employed for metabolic analysis and protein expression analysis. Results: In this study, CANA showed diuretic, hypotensive, weight loss, and increased intake of food and water. Dahl salt-sensitive (DSS) rats fed with a diet containing 8% NaCl AIN-76A developed left ventricular remodeling and diastolic dysfunction caused by hypertension. After CANA treatment, cardiac hypertrophy and fibrosis were reduced, and the left ventricular diastolic function was improved. Metabolomics and proteomics data confirmed that CANA reduced myocardial glucose metabolism and increased fatty acid metabolism and ketogenesis in DSS rats, normalizing myocardial metabolism and reducing the myocardial oxidative stress. Mechanistically, CANA upregulated p-adenosine 5'-monophosphate-activated protein kinase (p-AMPK) and sirtuin 1 (SIRT1) and significantly induced the expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1a). Conclusion: CANA can improve myocardial hypertrophy, fibrosis, and left ventricular diastolic dysfunction induced by hypertension in DSS rats, possibly through the activation of the AMPK/SIRT1/PGC-1a pathway to regulate energy metabolism and oxidative stress.

Keywords: canagliflozin; fibrosis; heart failure with preserved ejection fraction; hypertension; metabolism; myocardial hypertrophy.