SGLT2 inhibitor dapagliflozin attenuates cardiac fibrosis and inflammation by reverting the HIF-2α signaling pathway in arrhythmogenic cardiomyopathy.

Abstract

Excessive cardiac fibrosis and inflammation aberrantly contribute to the progressive pathogenesis of arrhythmogenic cardiomyopathy (ACM). Whether sodium-glucose cotransporter-2 inhibitor (SGLT2i), as a new hypoglycemic drug, benefits ACM remains unclear. Cardiomyocyte-specific Dsg2 exon-11 knockout and wild-type (WT) littermate mice were used as the animal model of ACM and controls, respectively. Mice were administered by gavage with either SGLT2i dapagliflozin (DAPA, 1 mg/kg/day) or vehicle alone for 8 weeks. HL-1 cells were treated with DAPA to identify the molecular mechanism in vitro. All mice presented normal glucose homeostasis. DAPA not only significantly ameliorated cardiac dysfunction, adverse remodeling, and ventricular dilation in ACM but also attenuated ACM-associated cardiac fibrofatty replacement, as demonstrated by the echocardiography and histopathological examination. The protein expressions of HIF-2α and HIF-1α were decreased and increased respectively in cardiac tissue of ACM, which were compromised after DAPA treatment. Additionally, NF-κB P65 and IκB phosphorylation, as well as fibrosis indicators (including TGF-β, α-SMA, Collagen I, and Collagen III) were increased in ACM. However, these trends were markedly suppressed by DAPA treatment. Consistent with these results in vitro, DAPA alleviated the IκB phosphorylation and NF-κB p65 transcriptional activity in DSG2-knockdown HL-1 cells. Interestingly, the elective HIF-2α inhibitor PT2399 almost completely blunted the DAPA-mediated downregulation of indicators concerning cardiac fibrosis and inflammation. SGLT2i attenuated the ACM-associated cardiac dysfunction and adverse remodeling in a glucose-independent manner by suppressing cardiac fibrosis and inflammation via reverting the HIF-2α signaling pathway, suggesting that SGLT2i is a novel and available therapy for ACM.

• Authors: Zhe Yang, Tengling Li, Jianzhong Xian, Jia Chen, Yin Huang, Qin Zhang, Xiufang Lin, Hongyun Lu, Yubi Lin
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 36 Issue 7 Pg. e22410 (07 2022) ISSN: 1530-6860 [Electronic] United States
• PMID: 35713937 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• Benzhydryl Compounds
• Glucosides
• NF-kappa B
• Sodium-Glucose Transporter 2 Inhibitors
• dapagliflozin
• Collagen
• Glucose

Topics

• Animals
• Basic Helix-Loop-Helix Transcription Factors (metabolism)
• Benzhydryl Compounds (pharmacology)
• Cardiomyopathies (drug therapy, etiology, metabolism)
• Collagen
• Diabetes Mellitus, Type 2 (drug therapy)
• Fibrosis
• Glucose
• Glucosides
• Heart Diseases
• Inflammation (drug therapy)
• Mice
• NF-kappa B (metabolism)
• Signal Transduction
• Sodium-Glucose Transporter 2 Inhibitors (pharmacology, therapeutic use)