Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, Kentucky, USA.
Am J Physiol Heart Circ Physiol. 2010 Feb;298(2):H451-6. doi: 10.1152/ajpheart.00682.2009. Epub 2009 Nov 20.
Reactive oxygen and nitrogen species (ROS and RNS, respectively) generate nitrotyrosine and activate latent resident myocardial matrix metalloproteinases (MMPs). Although in chronic heart failure (CHF) there is robust increase in ROS, RNS, and MMP activation, recent data suggest that hydrogen sulfide (H(2)S, a strong antioxidant gas) is cardioprotective. However, the role of H(2)S in mitigating oxidative and proteolytic stresses in cardiac remodeling/apoptosis in CHF was unclear. To test the hypothesis that H(2)S ameliorated cardiac apoptosis and fibrosis by decreasing oxidative and proteolytic stresses, arteriovenous fistula (AVF) was created in wild-type (C57BL/6J) mice. The hearts were analyzed at 0, 2, and 6 wk after AVF. To reverse the remodeling, AVF mice were treated with NaHS (an H(2)S donor, 30 micromol/l in drinking water) at 8 and 10 wk. The levels of MMPs were measured by gelatin-gel zymography. The levels of nitrotyrosine, tissue inhibitors of metalloproteinase (TIMPs), beta(1)-integrin, and a disintegrin and metalloproteinase-12 (ADAM-12) were analyzed by Western blots. The levels of pericapillary and interstitial fibrosis were identified by Masson trichrome stains. The levels of apoptosis were measured by identifying the TdT-mediated dUTP nick end labeling (TUNEL)-positive cells and caspase-3 levels. The results suggested robust nitrotyrosine and MMP activation at 2 and 6 wk of AVF. The treatment with H(2)S donor mitigated nitrotyrosine generation and MMP activation (i.e., oxidative and proteolytic stresses). The levels of TIMP-1 and TIMP-3 were increased and TIMP-4 decreased in AVF hearts. The treatment with H(2)S donor reversed this change in TIMPs levels. The levels of ADAM-12, apoptosis, and fibrosis were robust and integrin were decreased in AVF hearts. The treatment with H(2)S donor attenuated the fibrosis, apoptosis, and decrease in integrin.
活性氧和氮物种（ROS 和 RNS，分别）生成硝基酪氨酸并激活潜伏的心肌基质金属蛋白酶（MMPs）。虽然在慢性心力衰竭（CHF）中有强大的 ROS、RNS 和 MMP 激活，但最近的数据表明，硫化氢（H2S，一种强大的抗氧化气体）具有心脏保护作用。然而，H2S 在减轻 CHF 中心脏重塑/细胞凋亡中的氧化和蛋白水解应激中的作用尚不清楚。为了测试 H2S 通过降低氧化和蛋白水解应激来改善心脏细胞凋亡和纤维化的假说，在野生型（C57BL/6J）小鼠中创建动静脉瘘（AVF）。在 AVF 后 0、2 和 6 周分析心脏。为了逆转重塑，在 8 和 10 周时用 NaHS（H2S 供体，饮用水中 30 µm ol/L）治疗 AVF 小鼠。通过明胶凝胶酶谱法测量 MMP 水平。通过 Western blot 分析硝基酪氨酸、金属蛋白酶组织抑制剂（TIMPs）、β1-整合素和金属蛋白酶-12（ADAM-12）的水平。通过 Masson 三色染色鉴定毛细血管周围和间质纤维化水平。通过鉴定 TdT 介导的 dUTP 缺口末端标记（TUNEL）阳性细胞和 caspase-3 水平来测量细胞凋亡水平。结果表明，AVF 后 2 和 6 周时，硝基酪氨酸和 MMP 激活明显。H2S 供体的治疗减轻了硝基酪氨酸的产生和 MMP 激活（即氧化和蛋白水解应激）。AVF 心脏中的 TIMP-1 和 TIMP-3 水平增加，TIMP-4 减少。H2S 供体的治疗逆转了 TIMP 水平的这种变化。ADAM-12、细胞凋亡和纤维化水平在 AVF 心脏中明显增加，整合素减少。H2S 供体的治疗减轻了纤维化、细胞凋亡和整合素减少。
