SGK-1 Regulates Inflammation and Cell Death in the Ischemic-Reperfused Heart: Pressure-Related Effects
SGK-1 Regulates Inflammation and Cell Death in the Ischemic-Reperfused Heart: Pressure-Related Effects
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DOI：
10.1093/ajh/hpt269
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发表时间：
2014-06-01
影响因子：
3.2
通讯作者：
Mozaffari, Mahmood S.
中科院分区：
文献类型：
--
作者：
Baban, Babak;Liu, Jun Yao;Mozaffari, Mahmood S.
背景冠心病患者普遍存在全身性高血压和相关的心肌负荷/机械应力增加。因此，在心脏组织损伤的情况下确定细胞命运的机械敏感性分子机制的解开具有科学和临床意义。我们测试了这一假设，即促生存，机械敏感，血清糖皮质激素调节激酶-1（SGK-1）是一个关键的决定因素的压力相关的炎症反应和细胞命运在缺血-再灌注heart.METHODS Langendorff灌注大鼠心脏进行缺血再灌注（IR）的侮辱，在80或160厘米的水，用缺乏或含有SGK-1抑制剂GSK 650394 A（1 μ M）的灌注液;常氧心脏作为对照。然后，心脏组织用于蛋白质印迹或心脏细胞用于流式细胞术和免疫荧光研究。（活性和保护性）与线粒体膜电位（psi（m））的破坏以及凋亡和坏死的增加有关，以及（ii）生长停滞和DNA损伤相关蛋白153的表达增加（GADD 153;炎症和细胞死亡的决定因素）和促炎细胞因子白细胞介素（IL）17;这些影响在高压下更大。另一方面，抗炎细胞因子IL-10和IL-27在低压下的缺血再灌注心脏中增加更多。SGK-1抑制进一步减少磷酸化SGK-1，增加GADD 153和IL-17，并减少IL-10和IL-27与增强的破坏psi（m）和加剧细胞死亡，这些影响更大，在低pressure.CONCLUSIONS结果表明，主要的压力相关的作用，SGK-1在调节炎症和细胞的命运在缺血再灌注心脏。
BACKGROUND Systemic hypertension and the associated increased myocardial load/mechanical stress are common in patients with coronary heart disease. Thus, unraveling of mechanosensitive molecular mechanisms that determine cell fate in the setting of cardiac tissue injury is of scientific and clinical relevance. We tested the hypothesis that the prosurvival, mechanosensitive, serum glucocorticoid-regulated kinase-1 (SGK-1) is a pivotal determinant of pressure-related inflammatory response and cell fate in the ischemic-reperfused heart.METHODS Langendorff-perfused rat hearts were subjected to an ischemia reperfusion (IR) insult, at 80 or 160 cm water, with perfusate lacking or containing the SGK-1 inhibitor GSK650394A (1 mu M); normoxic hearts served as controls. Thereafter, hearts tissues were used for Western blotting or cardiac cells were prepared for flow cytometry and immunofluorescent studies.RESULTS An IR insult (i) reduced phosphoSGK-1 (active and protective) in association with disruption of mitochondrial membrane potential (psi(m)) and increased apoptosis and necrosis and (ii) increased expressions of growth-arrest and DNA damage-associated protein 153 (GADD153; a determinant of inflammation and cell death) and the proinflammatory cytokine interleukin (IL) 17; these effects were greater at high pressure. On the other hand, the anti-inflammatory cytokines IL-10 and IL-27 increased more in ischemic-reperfused hearts subjected to low pressure. SGK-1 inhibition further reduced phosphoSGK-1, increased GADD153 and IL-17, and reduced IL-10 and IL-27 in association with augmented disruption psi(m) and exacerbated cell death; these effects were greater at low pressure.CONCLUSIONS The results indicate a major pressure-related role for SGK-1 in regulating inflammation and cell fate in the ischemic-reperfused heart.