Empagliflozin Attenuates Cardiac Fibrosis by Suppressing Fibroblast-Mediated C-C Motif Chemokine Ligand 2 Expression

Area of Science:

• Cardiology
• Pharmacology
• Molecular Biology

Background:

• Heart failure (HF) is a leading cause of death and hospitalization, especially in older adults.
• Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce HF hospitalizations and cardiovascular death, but their mechanisms in non-diabetic patients are unclear.
• Understanding SGLT2 inhibitor mechanisms is crucial for developing new heart failure therapies.

Purpose of the Study:

• To investigate the cardiac-specific effects of SGLT2 inhibitors.
• To elucidate the mechanism by which SGLT2 inhibitors improve heart failure prognoses.
• To define the antifibrotic and anti-inflammatory actions of empagliflozin in heart failure.

Main Methods:

• Investigated empagliflozin's cardioprotective effects in mouse models of HF induced by transverse aortic constriction.
• Administered empagliflozin daily for two weeks post-constriction.
• Evaluated cardiac function, myocardial fibrosis, HF markers, macrophage infiltration, and chemokine expression.

Main Results:

• Empagliflozin preserved cardiac function and reduced myocardial fibrosis and HF markers.
• Empagliflozin decreased cardiac C-C chemokine receptor type 2-positive macrophages, indicating reduced inflammation.
• Empagliflozin reduced C-C motif chemokine ligand 2 expression in cardiac fibroblasts, modulating fibroblast behavior and inhibiting macrophage recruitment.

Conclusions:

• Proposed a novel antifibrotic mechanism where empagliflozin directly targets mechanically stressed cardiac fibroblasts.
• Empagliflozin reduces chemokine signaling and macrophage-mediated inflammation via fibroblast modulation.
• This fibroblast-targeted action represents a potential paradigm shift in understanding SGLT2 inhibitor cardioprotection for HF treatment.