硫化氢增强亚硝酸盐对 2 型糖尿病大鼠心肌缺血再灌注损伤的保护作用。

Hydrogen sulfide potentiates the protective effects of nitrite against myocardial ischemia-reperfusion injury in type 2 diabetic rats.

机构信息

Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Clinical Sciences in Malmö, Unit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Lund University, Malmö, Sweden.

出版信息

Nitric Oxide. 2022 Jul 1;124:15-23. doi: 10.1016/j.niox.2022.04.004. Epub 2022 Apr 30.

DOI:10.1016/j.niox.2022.04.004

PMID:35504499

Abstract

Decreased heart levels of nitric oxide (NO) and hydrogen sulfide (HS) in type 2 diabetes (T2D) are associated with a higher risk of mortality following ischemia-reperfusion (IR) injury. This study aimed to determine the effects of co-administration of sodium nitrite and sodium hydrosulfide (NaSH) on IR injury in the isolated heart from rats with T2D. Two-month-old male rats were divided into 5 groups (n = 7/group): Control, T2D, T2D + nitrite, T2D + NaSH, and T2D + nitrite + NaSH. T2D was induced using a high-fat diet and a single low dose streptozotocin (30 mg/kg) in intraperitoneal injection. Nitrite (50 mg/L in drinking water) and NaSH (0.28 mg/kg, daily intraperitoneal injection) were administrated for 9 weeks. At the end of the study, hemodynamic parameters were recorded, and infarct size and mRNA expression of HS- and NO-producing enzymes were measured in the isolated hearts. Nitrite administration to rats with T2D improved recovery of left ventricular developed pressure (LVDP) and the peak rates of positive and negative changes in LV pressure (±dp/dt) by 30%, 17%, and 7.9%, respectively, and decreased infarct size by 18.4%. Co-administration of nitrite and NaSH resulted in further improve in recovery of LVDP, +dp/dt, and -dp/dt by 8.3% (P = 0.0478), 8.4% (P = 0.0085), and 9.0% (P = 0.0004), respectively, and also further decrease in infarct size by 24% (P = 0.0473). Nitrite treatment decreased inducible and neuronal NO synthases (iNOS, 0.4-fold; nNOS, 0.4-fold) and cystathionine β-synthase (CBS, 0.1-fold) expression in the isolated heart from rats with T2D. Co-administration of nitrite and NaSH further increased cystathionine γ-lyase (CSE, 2.8-fold) and endothelial NOS (eNOS, 2.0-fold) expression and further decreased iNOS (0.4-fold) expression. In conclusion, NaSH at a low dose potentiates the favorable effects of inorganic nitrite against myocardial IR injury in a rat model of T2D. These anti-ischemic effects, following co-administration of nitrite and NaSH, were associated with higher CSE-derived HS and eNOS-derived NO as well as lower iNOS-derived NO in the diabetic hearts.

摘要

2 型糖尿病（T2D）患者心脏中一氧化氮（NO）和硫化氢（HS）水平降低与缺血再灌注（IR）损伤后死亡率升高有关。本研究旨在确定亚硝酸钠和硫氢化钠（NaSH）联合给药对 T2D 大鼠离体心脏 IR 损伤的影响。将 2 月龄雄性大鼠分为 5 组（每组 n = 7）：对照组、T2D 组、T2D+亚硝酸盐组、T2D+NaSH 组和 T2D+亚硝酸盐+NaSH 组。T2D 通过高脂肪饮食和单次低剂量链脲佐菌素（30mg/kg）腹腔注射诱导。亚硝酸盐（饮用水中 50mg/L）和 NaSH（0.28mg/kg，每日腹腔注射）给药 9 周。在研究结束时，记录离体心脏的血流动力学参数，并测量 HS 和 NO 产生酶的梗死面积和 mRNA 表达。亚硝酸盐给药可使 T2D 大鼠左心室发展压（LVDP）的恢复提高 30%、17%和 7.9%，左心室压力（±dp/dt）的正变化和负变化峰值分别提高 30%、17%和 7.9%，梗死面积减少 18.4%。亚硝酸钠和 NaSH 的联合给药可使 LVDP、+dp/dt 和-dp/dt 的恢复分别提高 8.3%（P = 0.0478）、8.4%（P = 0.0085）和 9.0%（P = 0.0004），梗死面积也进一步减少 24%（P = 0.0473）。亚硝酸盐处理降低了 T2D 大鼠离体心脏中诱导型和神经元型一氧化氮合酶（iNOS，0.4 倍；nNOS，0.4 倍）和胱硫醚β-合酶（CBS，0.1 倍）的表达。亚硝酸钠和 NaSH 的联合给药进一步增加了胱硫醚γ-裂合酶（CSE，2.8 倍）和内皮型一氧化氮合酶（eNOS，2.0 倍）的表达，并进一步降低了 iNOS（0.4 倍）的表达。总之，低剂量的 NaSH 增强了无机亚硝酸盐对 T2D 大鼠心肌 IR 损伤的有益作用。在 T2D 大鼠中，亚硝酸钠和 NaSH 联合给药的这些抗缺血作用与糖尿病心脏中更高的 CSE 衍生的 HS 和 eNOS 衍生的 NO 以及更低的 iNOS 衍生的 NO 有关。