Gamma-Oryzanol Attenuates Aortic Valve Interstitial Cell Calcification via Suppression of BMP2-SMAD and MAPK Signaling Pathways

Calcific aortic valve stenosis (CAVS) is a progressive cardiovascular disease associated with oxidative stress-driven osteogenic differentiation of valvular interstitial cells (VICs), yet no pharmacological therapy can prevent its progression. γ-oryzanol (γ-ORZ), a rice bran-derived phytosteryl ferulate, exhibits potent antioxidative and anti-inflammatory activities that may counteract valvular calcification. Here, we show that γ-ORZ markedly attenuates PCM-induced intracellular ROS elevation, osteogenic differentiation, and calcium phosphate deposition in porcine VICs (pVICs). In addition, RT-qPCR and Western blot analyses revealed significant downregulation of calcification markers (RUNX2, OPN, BMP2), along with suppressed SMAD1/5/9 transcription and phosphorylation, decreased p38/ERK MAPK activation, and reduced ALP activity. Collectively, these findings indicate that γ-ORZ mitigates oxidative stress-mediated valvular calcification by inhibiting both canonical and non-canonical BMP2-SMAD/MAPK signaling, suggesting its potential as a medicinal candidate for early intervention in CAVS.