Multi-omics insights into potential mechanism of SGLT2 inhibitors cardiovascular benefit in diabetic cardiomyopathy

Yangbo Xi; Dongping Chen; Zhihui Dong; Jinhua Zhang; Hingcheung Lam; Jiading He; Keyi Du; Can Chen; Jun Guo; Jianmin Xiao

doi:10.3389/fcvm.2022.999254

Multi-omics insights into potential mechanism of SGLT2 inhibitors cardiovascular benefit in diabetic cardiomyopathy

Front Cardiovasc Med. 2022 Oct 5:9:999254. doi: 10.3389/fcvm.2022.999254. eCollection 2022.

Authors

Yangbo Xi^{1

2}, Dongping Chen³, Zhihui Dong³, Jinhua Zhang¹, Hingcheung Lam¹, Jiading He¹, Keyi Du¹, Can Chen⁴, Jun Guo^{1

2}, Jianmin Xiao^{1

3

5}

Affiliations

¹ The First Clinical Medical College, Jinan University, Guangzhou, China.
² Department of Cardiology, The First Affiliated Hospital of Jinan University, Guangzhou, China.
³ Central Laboratory, Binhaiwan Central Hospital of Dongguan, The Dongguan Affiliated Hospital of Jinan University, Dongguan, China.
⁴ Department of Pathology, Binhaiwan Central Hospital of Dongguan, The Dongguan Affiliated Hospital of Jinan University, Dongguan, China.
⁵ Department of Cardiology, Binhaiwan Central Hospital of Dongguan, The Dongguan Affiliated Hospital of Jinan University, Dongguan, China.

Abstract

Background: Metabolic and energy disorders are considered central to the etiology of diabetic cardiomyopathy (DCM). Sodium-glucose cotransporter-2 inhibitors (SGLT2i) can effectively reduce the risk of cardiovascular death and heart failure in patients with DCM. However, the underlying mechanism has not been elucidated.

Methods: We established a DCM rat model followed by treatment with empagliflozin (EMPA) for 12 weeks. Echocardiography, blood tests, histopathology, and transmission electron microscopy (TEM) were used to evaluate the phenotypic characteristics of the rats. The proteomics and metabolomics of the myocardium in the rat model were performed to identify the potential targets and signaling pathways associated with the cardiovascular benefit of SGLT2i.

Results: The diabetic rat showed pronounced DCM characterized by mitochondrial pleomorphic, impaired lipid metabolism, myocardial fibrosis, and associated diastolic and systolic functional impairments in the heart. To some extent, these changes were ameliorated after treatment with EMPA. A total of 43 proteins and 34 metabolites were identified as targets in the myocardium of diabetic rats treated with EMPA. The KEGG analysis showed that arachidonic acid is associated with the maximum number of related pathways and may be a potential target of EMPA treatment. Fatty acid (FA) metabolism was enhanced in diabetic hearts, and the perturbation of biosynthesis of unsaturated FAs and arachidonic acid metabolism was a potential enabler for the cardiovascular benefit of EMPA.

Conclusion: SGLT2i ameliorated lipid accumulation and mitochondrial damage in the myocardium of diabetic rats. The metabolomic and proteomic data revealed the potential targets and signaling pathways associated with the cardiovascular benefit of SGLT2i, which provides a valuable resource for the mechanism of SGLT2i.

Keywords: SGLT2 inhibitors; diabetic cardiomyopathy; mechanisms; metabolomics; proteomics.