Targeting GATA6 with pedunculoside inhibits fetal gene expression to attenuate pathological cardiac hypertrophy.

Background: Pathological cardiac hypertrophy is a characteristic feature of numerous cardiovascular diseases and significantly impacts human health. However, effective treatment options for cardiac hypertrophy are still significantly unmet. Pedunculoside, a pentacyclic triterpenoid saponin from the traditional Chinese herb Ilex rotunda Thunb., exhibits various pharmacological properties such as anti-inflammatory and cardiovascular therapeutic effects, but its anti-hypertrophy efficacy and mechanisms have not yet been reported.

Purpose: This study aimed to confirm the ameliorating effect of pedunculoside on cardiac hypertrophy and elucidate its underlying mechanism.

Methods: To investigate the effect of pedunculoside on cardiac hypertrophy, we used transverse aortic constriction (TAC) and isoproterenol hydrochloride (ISO) infusion to induce cardiac hypertrophy model in mice. Angiotensin II (Ang II) was used to mimic hypertrophy model in myocardial cells. Then, we utilized a biotin-tagged carabrone chemical probe and validation experiments to pinpoint pedunculoside's key targets. Further, molecular docking study and sites mutation were used to predict and identify the binding modes of pedunculoside to target. Finally, structural optimization was carried out to find new pedunculoside derivatives with stronger anti-hypertrophy activity and binding affinity to the target.

Results: Our findings revealed for the first time that pedunculoside treatment significantly attenuated hypertrophic phenotypes in response to TAC and ISO. It also effectively reduced hypertrophy and fibrosis in myocardial cells exposed to Ang II stimulation. Mechanically, we identified transcription factor GATA-6 (GATA6) as a key target of pedunculoside for treating cardiac hypertrophy. Further studies demonstrated that pedunculoside blocks cardiac hypertrophy progression by inhibiting the transcriptional activation of GATA6 on promoting fetal gene expression. More importantly, a new pedunculoside derivative PE-3 with stronger anti-hypertrophy activity and affinity for GATA6 was discovered.

Conclusion: Our findings suggest that pedunculoside and PE-3 could be developed as promising drug candidates for cardiac hypertrophy treatment.