Comparison of the Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Cardiac Fibroblast Properties

Area of Science:

• Cardiology
• Pharmacology
• Cell Biology

Background:

• Sodium-glucose cotransporter 2 inhibitors (SGLT2i) demonstrate significant cardioprotective effects in clinical trials.
• These benefits extend to heart failure hospitalizations in both diabetic and non-diabetic individuals.
• The precise mechanisms of SGLT2i cardioprotection beyond glucose lowering are not fully understood.

Purpose of the Study:

• To investigate the direct effects of SGLT2 inhibitors on human cardiac fibroblasts.
• To compare the impact of canagliflozin, empagliflozin, and dapagliflozin on fibroblast behavior.
• To explore the role of AMP-activated protein kinase (AMPK) in mediating these cellular effects.

Main Methods:

• Primary human cardiac fibroblast cultures were utilized.
• The effects of canagliflozin, empagliflozin, and dapagliflozin on myofibroblast differentiation, proliferation, and migration were assessed.
• AMPK phosphorylation and the impact of an AMPK inhibitor (BAY-3827) were examined.

Main Results:

• All tested SGLT2 inhibitors prevented myofibroblast differentiation.
• Canagliflozin uniquely inhibited cardiac fibroblast proliferation and migration.
• While all SGLT2i increased AMPK phosphorylation, myodifferentiation effects were AMPK-independent, whereas canagliflozin's migration effects were partially AMPK-dependent.

Conclusions:

• Individual SGLT2 inhibitors exhibit distinct cellular effects on cardiac fibroblasts.
• These differences suggest varied potential in modulating extracellular matrix remodeling and myocardial fibrosis.
• Canagliflozin may possess a more potent capacity to prevent cardiac fibrosis in heart failure contexts.