J Am Heart Assoc. 2026 Apr 16:e045304. doi: 10.1161/JAHA.125.045304. Online ahead of print.
ABSTRACT
BACKGROUND: High salt (HS) intake is a known cardiovascular risk factor, yet the mechanisms linking salt intake to endothelial dysfunction remain unclear. We investigated whether HS induces vascular senescence and dysfunction, and whether targeting senescent cells could prevent these effects.
METHODS: Male C57BL/6J mice were fed a high-salt diet (HSD [8% NaCl]) for 14 or 28 days. Vascular function was assessed in thoracic aortae and mesenteric arteries using wire myography. Senescence was evaluated by p21, p16, and interleukins (IL) 6 and 1β expression in endothelial cells and whole vessels. To test reversibility, mice received the senolytic drug navitoclax.
RESULTS: A 28-day, but not 14-day, HSD caused endothelial dysfunction and increased vascular senescence markers, indicating senescence. Navitoclax treatment reduced senescence markers, restored vasodilation of mesenteric arteries, and improved vascular contractility. HSD exposure elevated inflammatory gene expression in peritoneal immune cells and increased circulating levels of interleukin-16 (IL16). Thus, we treated mesenteric arteries and mesenteric endothelial cells with recombinant IL16 to analyze whether HSD can induce vascular dysfunction via senescence. IL16 caused endothelial dysfunction and increased p21 expression.
CONCLUSIONS: Prolonged HSD intake induces vascular senescence and dysfunction via immune activation rather than direct endothelial dysfunction, while senolytic therapy prevents HSD-induced vascular dysfunction. Targeting senescence or inflammation, particularly IL16 signaling, may offer new therapeutic strategies for salt-sensitive vascular diseases.
PMID:41988978 | DOI:10.1161/JAHA.125.045304