Aldosterone-induced inflammation in the rat heart - Role of oxidative stress
Aldosterone-induced inflammation in the rat heart - Role of oxidative stress
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DOI：
10.1016/s0002-9440(10)64454-9
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发表时间：
2002-11-01
影响因子：
6
通讯作者：
Weber, KT
中科院分区：
文献类型：
--
作者：
Sun, Y;Zhang, JK;Weber, KT
心力衰竭和高血压都与神经激素（如血管紧张素II和儿茶酚胺）引起的氧化应激诱导有关。在此，我们假设醛固酮（ALDO）同样诱导氧化应激，并解释了在ALDO/盐治疗后右心室和左心室血管和非血管损伤部位出现的促炎/纤维化表型，这种表型将在慢性治疗中持续存在。未去肾大鼠接受ALDO（0.75杯/小时）和1%膳食NaCl，持续3、4或5周。其他组联合使用ALDO受体拮抗剂螺内酯（200mg /kg每日一次）或抗氧化剂，二硫代氨基甲酸吡啶（PDTC） （200mg /kg s.c. daffy）或n -乙酰半胱氨酸（NAC） （200mg /kg每日一次）。未手术和未治疗的年龄和性别匹配的大鼠作为对照。我们使用左、右心室的连续冠状切片来监测分子和细胞事件的空间和时间反应。我们的研究包括：收缩压评估；免疫组化检测NADPH氧化酶的表达和活性，分析氧化还原敏感核因子κ b的活化；细胞间粘附分子-1、单核细胞趋化蛋白-1和肿瘤坏死因子-a mRNA的原位定位表达；监测巨噬细胞和T细胞的生长和浸润；并分析了纤维组织堆积的形态和数量。在ALDO/盐治疗的第3周，与对照组相比，心脏中没有氧化应激或病理结果的证据。然而，在治疗的第4周和第5周，在冠状动脉壁内血管周围间隙和两个心室心肌细胞丢失部位的内皮细胞和炎症细胞中发现gp91（phox）和3-硝基酪氨酸表达增加，RelA持续激活。细胞间黏附分子-1、单核细胞趋化蛋白-1和肿瘤坏死因子-a mRNA的表达在时间和空间上均呈上升趋势。巨噬细胞、淋巴细胞、增殖的内皮细胞和血管平滑肌细胞以及成纤维细胞样细胞均出现在这些部位，并伴有纤维性胶原的积累，或纤维化，心室胶原体积分数显著增加。与螺内酯、PDTC或NAC联合治疗可减轻这些分子和细胞反应以及血管和非血管损伤部位的纤维化。此外，经aldo处理的大鼠收缩压升高被螺内酯或任一抗氧化剂部分抑制。因此，慢性ALDO/盐处理伴随着NADPH氧化酶的时间依赖性持续激活，3-硝基酪氨酸生成和内皮细胞和炎症细胞表达的核因子κ b激活。这导致了促炎/纤维化表型，分别涉及血管和非血管部位的损伤，在血压正常和高血压的右心室和左心室。Spionolactone， PDTC和NAC各自减弱了这些反应，表明ALDO/盐诱导氧化/亚硝化应激是导致这种促炎表型出现的原因。
Heart failure and hypertension have each been linked to an induction of oxidative stress transduced by neurohormones, such as angiotensin II and catecholamines. Herein, we hypothesized that aldosterone (ALDO) likewise induces oxidative stress and accounts for a proinflammatory/fibrogenic phenotype that appears at vascular and nonvascular sites of injury found in both right and left ventricles in response to ALDO/salt treatment and that would be sustained with chronic treatment. Uninephrectomized rats received ALDO (0.75 mug/hour) together with 1% dietary NaCl, for 3, 4, or 5 weeks. Other groups received this regimen in combination with an ALDO receptor antagonist, spironolactone (200 mg/kg p.o. daily), or an antioxidant, either pyrrolidine dithiocarbamate (PDTC) (200 mg/kg s.c. daffy) or N-acetylcysteine (NAC) (200 mg/kg i.p. daily). Unoperated and untreated age- and gender-matched rats served as controls. We monitored spatial and temporal responses in molecular and cellular events using serial, coronal sections of right and left ventricles. Our studies included: assessment of systolic blood pressure; immunohistochemical detection of NADPH oxidase expression and activity, analysis of redox-sensitive nuclear factor-kappaB activation; in situ localization of intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and tumor necrosis factor-a mRNA expression; monitoring cell growth and infiltration of macrophages and T cells; and analysis of the appearance and quantity of fibrous tissue accumulation. At week 3 of ALDO/salt treatment and comparable to controls, there was no evidence of oxidative stress or pathological findings in the heart However, at weeks 4 and 5 of treatment, increased gp91(phox) and 3-nitrotyrosine expression and persistent activation of RelA were found in endothelial cells and inflammatory cells that appeared in the perivascular space of intramural coronary arteries and at sites of lost cardiomyocytes in both ventricles. Coincident in time and space with these events was increased mRNA expression of intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and tumor necrosis factor-a. Macrophages, lymphocytes, and proliferating endothelial and vascular smooth muscle cells and fibroblast-like cells were seen at each of these sites, together with an accumulation of fibrillar collagen, or fibrosis, as evidenced by a significant increase in ventricular collagen volume fraction. Co-treatment with spironolactone, PDTC, or NAC attenuated these molecular and cellular responses as well as the appearance of fibrosis at vascular and nonvascular sites of injury. Furthermore, elevated systolic blood pressure in ALDO-treated rats was partially suppressed by spironolactone or either antioxidant. Thus, chronic ALDO/salt treatment is accompanied by a time-dependent sustained activation of NADPH oxidase with 3-nitrotyrosine generation and nuclear factor-kappaB activation expressed by endothelial cells and inflammatory cells. This leads to a proinflammatory/fibrogenic phenotype involving vascular and nonvascular sites of injury found, respectively, in both normotensive and hypertensive right and left ventricles. Spionolactone, PDTC, and NAC each attenuated these responses suggesting ALDO/salt induction of oxidative/nitrosative stress is responsible for the appearance of this proinflammatory phenotype.