ASK1 Inhibition by Selonsertib Attenuates Vascular Smooth Muscle Cell Activation and Modulates Inflammatory Cytokines, Metabolic Parameters, and Cardiac Function in HFHSD-Induced Obesity

Background: Vascular smooth muscle cell (VSMC) phenotypic switching drives vascular remodeling in cardiovascular diseases and metabolic dysfunction. Apoptosis signal-regulating kinase 1 (ASK1) mediates oxidative stress and inflammatory signaling. We investigated the effects of ASK1 inhibition by selonsertib on VSMC activation in vitro and metabolic/cardiovascular parameters in vivo.

Methods: A7r5 VSMCs were treated with angiotensin II (Ang II, 300 nM) with or without selonsertib (0,02 µM). Intracellular ROS, NF-κB, and Nrf2/ARE promoter activities were evaluated. In vivo (CEUA/UFRJ 094/24), female C57BL/6 mice were fed a high-fat high-sucrose diet (HFHSD) for 27 weeks and treated daily with selonsertib (2 or 20 mg/kg) or vehicle for 30 days. Body weight, food intake, glycemic profile (fasting glucose, OGTT, ITT), systemic cytokines (MCP-1, IL-1β, IL-6, IL-10), tissue mass, and ejection fraction (EF) were evaluated.

Results: In VSMCs, selonsertib (0.02 µM) inhibited Ang II-induced viability increases and intracellular ROS generation, while decreasing Ang II-stimulated NF-κB and Nrf2/ARE reporter activities. In vivo, HFHSD induced obesity, hyperglycemia, and reduced cardiac EF compared to controls. Treatment with selonsertib (20 mg/kg) significantly reduced body weight gain during treatment without affecting food or caloric intake. Selonsertib (20 mg/kg) restored cardiac EF in HFHSD mice. Systemically, selonsertib decreased circulating inflammatory cytokines IL-1β and MCP-1 levels in HFHSD mice, whereas IL-6 and IL-10 showed minimal alterations.

Conclusion: ASK1 inhibition by selonsertib reduces VSMC oxidative stress and NF-κB activation in vitro, while decreasing body weight gain, systemic inflammatory cytokines (IL-1β, MCP-1), and cardiac dysfunction in vivo, establishing ASK1 as a key target in vascular inflammation and metabolic dysfunction.

References: Cardiovasc. Res. (2013) 97:134; Int. Heart J. (2018) 59:1416; Am. J. Pathol. (2013) 182:597.