Salt-induced vascular damage in hypertension involves redox activation of PARP/TRPM2 signalling and inflammasome assembly

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Alves-Lopes, Rheure and Neves, Karla B and Mary, Sheon and Graham, Delyth and Montezano, Augusto C and Delles, Christian and Touyz, Rhian M (2025) Salt-induced vascular damage in hypertension involves redox activation of PARP/TRPM2 signalling and inflammasome assembly. American Journal of Hypertension, 38 (10). pp. 788-796. ISSN 1941-7225 (https://doi.org/10.1093/ajh/hpaf071)

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Abstract

BACKGROUND Excess sodium intake induces vascular dysfunction. Molecular mechanisms underlying this are unclear. Here we investigated the role of reactive oxygen species (ROS), Ca2+ signaling and inflammation in salt-induced vascular injury, focusing on the interplay between redox-sensitive Poly(ADP-ribose) polymerase (PARP), which activates transient receptor potential melastatin 2 (TRPM2) Ca2+ channel, and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome. Specifically, we sought to determine if salt excess induces a pro-oxidant environment, leading to PARP-induced TRPM2 activation and increased Ca2+ influx, inflammasome assembly, and consequent vascular damage. METHODS Vascular smooth muscle cells (VSMCs) from rats and humans were exposed to normal NaCl (140 mM) and high-salt conditions (180 mM). RESULTS High salt increased ROS generation, PARP activation, and TRPM2-mediated Ca2+ transients. Osmotic controls had no effect on these processes. High-salt medium promoted the release of pro-inflammatory cytokines interleukin-18 and interleukin-1β and increased phosphorylation of myosin light chain (MLC) in VSMCs. These effects were attenuated by inhibitors of PARP (Olaparib), TRPM2 (8-Br-cADPR), and NLRP3 inflammasome (MCC950). To validate these findings in in vivo, mice were subjected to a high-salt diet (4% NaCl, 5 weeks), resulting in elevated blood pressure and vascular remodeling and dysfunction. Exposure of vessels to olaparib and MCC950 attenuated the hypercontractility associated with a high-salt diet. CONCLUSIONS Salt-induced vascular injury in hypertension involves ROS generation in VSMCs leading to activation of the PARP/TRPM2 axis, increased Ca2+ influx, NLRP3 activation, and vascular injury. Our study provides new insights into molecular pathways involved in high-salt diet-induced vascular dysfunction, important in hypertension.

ORCID iDs

Alves-Lopes, Rheure, Neves, Karla B ORCID logoORCID: https://orcid.org/0000-0001-5158-9263, Mary, Sheon, Graham, Delyth, Montezano, Augusto C, Delles, Christian and Touyz, Rhian M;
CORE (COnnecting REpositories)