Institute of Normal and Pathological Physiology, Centre of Experimental Medicine, Slovak Academy of Sciences, 841-04 Bratislava, Slovakia.
Department of Animal Physiology and Ethology, Faculty of Natural Sciences, Comenius University, 841-04 Bratislava, Slovakia.
Int J Mol Sci. 2022 Aug 16;23(16):9215. doi: 10.3390/ijms23169215.
Increased fructose consumption induces metabolic-syndrome-like pathologies and modulates vasoactivity and the participation of nitric oxide (NO) and hydrogen sulfide (HS). We investigated whether a slow-releasing HS donor, GYY-4137, could exert beneficial activity in these conditions. We examined the effect of eight weeks of fructose intake on the blood pressure, biometric parameters, vasoactive responses, and NO and HS pathways in fructose-fed spontaneously hypertensive rats with or without three weeks of GYY-4137 i.p. application. GYY-4137 reduced triacylglycerol levels and blood pressure, but not adiposity, and all were increased by fructose intake. Fructose intake generally enhanced endothelium-dependent vasorelaxation, decreased adrenergic contraction, and increased protein expression of interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα), and concentration of conjugated dienes in the left ventricle (LV). Although GYY-4137 administration did not affect vasorelaxant responses, it restored disturbed contractility, LV oxidative damage and decreased protein expression of TNFα in fructose-fed rats. While the participation of endogenous HS in vasoactive responses was not affected by fructose treatment, the expression of HS-producing enzyme cystathionine β-synthase in the LV was increased, and the stimulation of the NO signaling pathway improved endothelial function in the mesenteric artery. On the other hand, chronic treatment with GYY-4137 increased the expression of HS-producing enzyme cystathionine γ-lyase in the LV and stimulated the beneficial pro-relaxant and anti-contractile activity of endogenous HS in thoracic aorta. Our results suggest that sulfide and nitroso signaling pathways could trigger compensatory vasoactive responses in hypertensive rats with metabolic disorder. A slow HS-releasing donor could partially amend metabolic-related changes and trigger beneficial activity of endogenous HS.
摄入过多的果糖会导致代谢综合征样病变，并调节血管活性以及一氧化氮（NO）和硫化氢（HS）的参与。我们研究了一种缓慢释放的 HS 供体 GYY-4137 是否能在这些情况下发挥有益的作用。我们检测了 8 周的果糖摄入对血压、生物计量参数、血管活性反应以及有无 GYY-4137 腹腔注射 3 周的果糖喂养自发性高血压大鼠中 NO 和 HS 途径的影响。GYY-4137 降低了三酰甘油水平和血压，但不能降低肥胖，所有这些都是果糖摄入引起的。果糖摄入通常增强了内皮依赖性血管舒张，降低了肾上腺素能收缩，并增加了左心室（LV）中白细胞介素 6（IL-6）、肿瘤坏死因子 α（TNFα）和共轭二烯浓度的蛋白表达。尽管 GYY-4137 给药不影响血管舒张反应，但它恢复了果糖喂养大鼠的收缩功能障碍、LV 氧化损伤和 TNFα 蛋白表达的降低。虽然 HS 内源性参与血管活性反应不受果糖处理的影响，但 LV 中 HS 产生酶半胱氨酸 β-合酶的表达增加，并且 NO 信号通路的刺激改善了肠系膜动脉的内皮功能。另一方面，慢性 GYY-4137 治疗增加了 LV 中 HS 产生酶半胱氨酸 γ-裂合酶的表达，并刺激了内源性 HS 的有益的促舒张和抗收缩活性。我们的结果表明，硫化物和亚硝酰信号通路可能触发代谢紊乱的高血压大鼠的代偿性血管活性反应。一种缓慢释放的 HS 供体可以部分纠正与代谢相关的变化，并触发内源性 HS 的有益活性。
