HYDROGEN SULFIDE-RELEASING ANTI-INFLAMMATORY DRUG ATB-340 TREATMENT POTENTIALLY REDUCES MESENTERIC METAFLAMMATION IN THE EXPERIMENTAL AGE- AND HIGH FRUCTOSE DIETARY-INDUCED INJURY

Abstract

Metaflammation (MF) is associated with visceral adiposities involved in the metabolic, cardiovascular, and gastrointestinal disease pathogenesis while their target therapeutic strategy is still limited. The link between mesenteric white adipocytes (MA) and stromal-vascular cellular remodeling in advanced age and Western diet consumption which is the base of MF remain undiscovered. Hydrogen Sulfide (H₂S) non-steroidal anti-inflammatory drugs (H₂S-NSAIDs) are a promising novel class of drugs regarding their cytoprotective, regulatory redox signaling, vasodilatory, and anti-inflammatory effects.

Aim. To study the effectiveness of novel H₂S-NSAIDs ATB-340, a hybrid compound of H₂S and aspirin (ASA) over conventional ASA, and combination of ASA and NaHS on mesenteric cellular adaptive changes in experimental age- and high fructose dietary (HFD)-induced injury.

Methods: Mesenteric subcellular adaptive responses of aged male rats on a standard diet (SD) or 4 weeks HFD that underwent acute water-immersion restraint stress (WIRS) were evaluated by electron microscopy. The effects of 9 days exogenous administration of ATB-340 (17.5 mg/kg/day), ASA (10 mg/kg/day) and sodium hydrosulfide (NaHS, 5.6 mg/kg/day) were investigated. Serum glucose level, thiobarbituric acid reactive substances (TBARS), and activities of cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS), thiosulfate-dithiol sulfurtransferase (TST), and sulfite oxidase (SO) were examined biochemically using spectrophotometry.

Results: In HFD groups exposed to WIRS treatment with ATB-340 protected MA, as well their mitochondria, microvascular endothelial, and sub-endothelial structures, fibroblasts were observed vs the ASA and H₂S+ASA-treated groups that had signs of endothelial dysfunction, MA damage with dysfunctional mitochondria, and mitochondria with fat incorporation. In rats fed with HFD and ASA treatment, low activities of CSE, CBS, TST and the rise of TBARS level and SO activity were observed. Treatment with ASA+NaHS, ATB-340 of aged rats lowered TBARS and enhanced H₂S enzyme activities in contrast to the vehicle-treated group (p < 0.05).

Conclusions. Mitochondrial alterations, endothelial damage, and redox disbalance are key factors for aged rat mesenteric adipose tissue remodeling during Western diet consumption. Our results contributing to identifying powerful intervention by effective compound H₂S-ASA, novel H₂S-NSAIDs, which has the potential to modulate mesenteric metaflammation, vascular function by enhancement H₂S synthesis and redox regulatory and cytoprotective activities