What is the clinical evidence from this study?

Study design: Other. Population: Cardiac remodeling. Intervention: Dapagliflozin vs. Control/Sham. Primary outcome: Cardiac remodeling and ALDH2 expression.

October 26, 2024Cardiovascular Diabetology10 citationsOpen Access

ALDH2 mediates the effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on improving cardiac remodeling

HLHan Liu BJBin Jiang RHRui Hua

Key Result

Dapagliflozin protects against cardiac remodeling by upregulating ALDH2 expression through the NHE1/ROS/DNMT1 pathway.

Structured PICO

Does dapagliflozin prevent cardiac remodeling in preclinical models of cardiac hypertrophy?

Population

Translational study using mouse models of cardiac hypertrophy, cell cultures, and peripheral blood mononuclear cells from patients with type 2 diabetes to investigate the mechanisms of dapagliflozin.

Intervention

Dapagliflozin (1 mg/kg/d intragastric in mice; 10 mg/d orally for 3 days in human patients; 5-20 µM in vitro).

Comparator

Sham operation, vehicle control, or untreated cells/mice.

Outcome

Cardiac remodeling (assessed by heart weight ratios, echocardiography, and histological fibrosis/hypertrophy) and ALDH2 expression/activity.surrogate

Dapagliflozin protects against cardiac remodeling by upregulating ALDH2 via the NHE1/ROS/DNMT1 pathway, providing a novel mechanistic explanation for the benefits of SGLT2 inhibitors in heart failure.

Limitations

Reliance on animal and in vitro models for mechanistic findings.

Abstract

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are now recommended for patients with heart failure, but the mechanisms that underlie the protective role of SGLT2i in cardiac remodeling remain unclear. Aldehyde dehydrogenase 2 (ALDH2) effectively prevents cardiac remodeling. Here, the key role of ALDH2 in the efficacy of SGLT2i on cardiac remodeling was studied. METHODS: ) were generated to determine the critical role of ALDH2 in the preventive effects of dapagliflozin (DAPA) on cardiac remodeling. RNA sequencing, gene knockdown or overexpression, bisulfite sequencing PCR, and luciferase reporter assays were performed to explore the underlying molecular mechanisms involved. RESULTS: Only ALDH2 was differentially expressed when the differentially expressed genes obtained via Mendelian analysis and the differentially expressed genes obtained from the multiple transcriptome datasets were combined. Mendelian analysis revealed that ALDH2 was negatively related to the severity of myocardial hypertrophy in patients. DAPA alleviated cardiac remodeling in mouse hearts subjected to TAC or ISO. ALDH2 expression was reduced, whereas ALDH2 expression was restored by DAPA in hypertrophic hearts. Cardiomyocyte specific ALDH2 knockout abolished the protective role of DAPA in preventing cardiac remodeling. ALDH2 expression and activity were increased in DAPA-treated neonatal rat primary cardiomyocytes (NRCMs), H9C2 cells and AC16 cells. Moreover, DAPA upregulated ALDH2 in peripheral blood mononuclear cells (PBMCs) from patients with type 2 diabetes. Sodium/proton exchanger 1 (NHE1) inhibition contributed to the regulation of ALDH2 by DAPA. DAPA suppressed the production of reactive oxygen species (ROS), downregulated DNA methyltransferase 1 (DNMT1) and subsequently reduced the ALDH2 promoter methylation level. Further studies revealed that DAPA enhanced the binding of nuclear transcription factor Y, subunit A (NFYA) to the promoter region of ALDH2, which was due to the decreased promoter methylation level of ALDH2. CONCLUSIONS: The upregulation of ALDH2 plays a critical role in the protection of DAPA against cardiac remodeling. DAPA enhances the binding of NFYA to the ALDH2 promoter by reducing the ALDH2 promoter methylation level through NHE1/ROS/DNMT1 pathway.

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