Empagliflozin inhibits cardiac hypertrophy via a mechanism involving integrin signalling
Abstract
BACKGROUND AND PURPOSE
Pathological cardiac hypertrophy precipitates heart failure. Empagliflozin (EMPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, confers cardiovascular protection beyond glycaemic control, but the molecular basis of its direct anti-hypertrophic action remains undefined.
EXPERIMENTAL APPROACH
Angiotensin II (Ang II)-induced hypertrophy was modelled in AC16 and H9c2 cardiomyocytes, and pressure overload was modelled in mice undergoing transverse aortic constriction (TAC). Outcomes were assessed by cell surface area, marker expression, histology and echocardiography. Mechanistic studies included transcriptomic profiling, integrin subunit analysis, pharmacological integrin blockade with ATN-161, downstream signalling, in silico EMPA-SP1 docking and SP1 knockdown. Blood glucose, body weight and urinary glucose were monitored.
KEY RESULTS
EMPA attenuated Ang II-induced cardiomyocyte hypertrophy in vitro and TAC-induced dysfunction, hypertrophy and interstitial fibrosis in vivo. Transcriptomic analysis revealed enrichment of extracellular matrix-receptor interaction, focal adhesion and cytoskeleton pathways, implicating integrin signalling. TAC up-regulated integrin subunits, which EMPA normalized. ATN-161 abrogated EMPA-mediated suppression of hypertrophic readouts and restored FAK/Src/Akt activation, demonstrating functional integrin dependency. Docking predicted a high-affinity EMPA-SP1 interaction; SP1 knockdown reduced basal integrin expression and…
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