Cardioprotective effect of tamoxifen and raloxifene: Preventing proteoglycan synthesis by modulating non-canonical TGF-0 signalling through NADPH oxidase and ERK phosphorylation

Atherosclerosis, a leading cause of cardiovascular disease, remains a significant global health concern. Tamoxifen and raloxifene, selective estrogen receptor modulators (SERMs), have demonstrated potential cardioprotective effects. However, the underlying molecular mechanisms by which these SERMs modulate Transforming Growth Factor-0 (TGF-0) signaling in human vascular smooth muscle cells (VSMCs) remain largely unexplored. This study sought to investigate the impact of tamoxifen and ral-oxifene on TGF-0-induced CHSY1 expression and Smad2 linker region phosphorylation in VSMCs and to elucidate the role of reactive oxygen species (ROS), NADPH oxidase (NOX), and kinase pathways in mediating these effects.Employing a comprehensive experimental strategy, VSMCs were treated with TGF-0 in the presence or absence of tamoxifen, raloxifene, and various pharmacological inhibitors. Subsequently, CHSY1 mRNA expression, Smad2C and Smad2L phosphorylation, ROS production, p47phox and ERK 1/2 phosphory-lation were assessed. Our results revealed that tamoxifen and raloxifene significantly attenuated TGF-0-mediated CHSY1 mRNA expression and Smad2 linker region phosphorylation, without affecting the canonical TGF-0-Smad2C pathway. Furthermore, these compounds effectively inhibited ROS production, p47phox and ERK 1/2 phosphorylation, implicating the involvement of the TGF-0-NOX-ERK-Smad2L signaling cascade in their cardioprotective properties. This study provides a comprehensive understanding of the molecular mechanisms underlying the cardioprotective effects of tamoxifen and raloxifene in VSMCs, offering valuable insights for the devel-opment of targeted therapeutic strategies aimed at atherosclerosis prevention and the promotion of cardiovascular health.& COPY; 2023 Elsevier Inc. All rights reserved.