Bisphenol S-induced cardiac remodeling is associated with an imbalance in the renin-angiotensin system

Cardiovascular diseases (CVD) are the leading cause of death worldwide, and cardiac remodeling is a key pathological feature. The renin–angiotensin system (RAS) plays a central role in CVD, but whether different doses of bisphenol S (BPS) modulate cardiac RAS remain unclear. Adult male C57BL/6 mice were assigned to control (C) or 4 (B4), 25 (B25), and 50 (B50) μg/kg/day of BPS in drinking water for 12 weeks. Body mass (BM), plasma cholesterol, left ventricle (LV) and cardiomyocyte morphology, RAS components and signaling markers, and remodeling mediators were assessed. B4 and B25 increased BM and plasma cholesterol, with a higher cardiac risk ratio. Regarding the RAS, all BPS doses overactivated the classical axis, evidenced by increased ACE activity and protein expression, and greater AT1R immunostaining, while suppressing the counterregulatory axis, with reduced ACE2 activity and protein expression and lower Mas receptor immunostaining. AT1R-related intracellular signaling (NOX2, NOX4, ERK 1/2 protein expression) increased in all groups. B4 and B25 presented ER stress, with increased GRP78 and CHOP protein expression, and ATF4 protein expression increased in all groups. B4 and B25 promoted pathological cardiac hypertrophy, with increased LV mass, wall thickness, chamber area and ANP protein expression. Inflammation markers protein expression was observed in all groups, particularly B4 and B25. All doses induced a pro-fibrotic profile with increased collagen deposition and TGFβ protein expression, more pronounced in B50. Overall, exposure to different BPS doses shifted the RAS activation towards the classical axis. These findings underscore the need for public policies regulating BPS. • Adult male mice were exposed to 4, 25, or 50 μg/kg/day of Bisphenol S • Cardiac morphology, renin angiotensin system and remodeling pathways were evaluated • Bisphenol S favored the classical axis of the renin angiotensin system • Bisphenol S activated AT1R-related oxidative and endoplasmic reticulum stress • Different doses of Bisphenol S promoted cardiac remodeling