Genetic deletion of calcium/calmodulin-dependent protein kinase kinase β (CaMKK β) or CaMK IV exacerbates stroke outcomes in ovariectomized (OVXed) female mice.
Genetic deletion of calcium/calmodulin-dependent protein kinase kinase β (CaMKK β) or CaMK IV exacerbates stroke outcomes in ovariectomized (OVXed) female mice.
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DOI：
10.1186/s12868-014-0118-2
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发表时间：
2014-10-21
期刊：
影响因子：
2.4
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Liu L;McCullough L;Li J
中风是美国长期残疾的主要原因。有趣的是，越来越多的证据表明，患者对中风治疗的反应存在潜在的性别差异，因为至少在一定程度上，中风后女性和男性可能会触发不同的细胞死亡程序。美国国立卫生研究院 (NIH) 认识到，女性在临床前试验中的代表性明显不足。钙/钙调蛋白依赖性蛋白激酶激酶 (CaMKK) 是一种由细胞内钙升高激活的主要激酶。最近有人提出，CaMKK 和 CaMK IV（下游靶分子）对男性中风具有神经保护作用。在这项研究中，我们检查了卵巢切除的 CaMKK β 和 CaMK IV 缺陷女性的中风结果。评估细胞死亡/存活信号和炎症反应。我们的结果表明，CaMKK β 或 CaMK IV KO 会加剧雌性小鼠的缺血性损伤和行为缺陷。 CaMKK β 或 CaMK IV 的基因缺失会增加中风后的出血性转化，这与 MMP9 活性增加和血脑屏障 (BBB) 蛋白胶原 IV 的丧失有关。在缺乏 CaMKK β 或 CaMK IV 的小鼠中观察到转录失活，磷酸化 cAMP 反应元件结合蛋白 (p-CREB) 和 B 细胞淋巴瘤 2 (BCL-2) 蛋白水平降低表明。最后，抑制该通路会加剧对中风的炎症反应，因为 CaMKK β 或 CaMK IV KO 小鼠在中风后促炎血清细胞因子肿瘤坏死因子 α (TNFα) 和白细胞介素 6 (IL-6) 的水平升高。这表明 CaMKK 通路参与脑损伤的免疫反应。 CaMKK 信号传导的抑制会加剧中风结果，并增加中风后女性的 BBB 损伤、转录失活和炎症反应。因此，CaMKK 信号传导可能是男性和女性中风治疗的潜在靶点。本文的在线版本 (doi:10.1186/s12868-014-0118-2) 包含补充材料，可供授权用户使用。
Stroke is the primary cause of long-term disability in the United States. Interestingly, mounting evidence has suggested potential sex differences in the response to stroke treatment in patients as, at least in part, distinct cell death programs may be triggered in females and males following stroke. The NIH has recognized that females are strikingly under-represented in pre-clinical trials. Calcium/calmodulin-dependent protein kinase kinase (CaMKK) is a major kinase that is activated by elevated intracellular calcium. It has recently been suggested that CaMKK and CaMK IV, a downstream target molecule, are neuroprotective in stroke in males. In this study, we examined stroke outcomes in ovariectomized CaMKK β and CaMK IV deficient females. Cell death/survival signaling and inflammatory responses were assessed. Our results demonstrated that CaMKK β or CaMK IV KO exacerbated both ischemic injury and behavioral deficits in female mice. Genetic deletion of CaMKK β or CaMK IV increased hemorrhagic transformation after stroke, and this was associated with both increased MMP9 activity and loss of the blood brain barrier (BBB) protein collagen IV. Transcriptional inactivation was observed in mice lacking either CaMKK β or CaMK IV, as indicated by reduced levels of phosphorylated cAMP response element-binding protein (p-CREB) and B-cell lymphoma 2 (BCL-2) proteins. Finally, inhibiting this pathway exacerbated the inflammatory response to stroke as CaMKK β or CaMK IV KO mice had increased levels of the pro-inflammatory serum cytokines tumor necrosis factor alpha (TNFα) and interleukin 6 (IL-6) after stroke. This suggests that the CaMKK pathway is involved in the immune response to brain injury. Inhibition of CaMKK signaling exacerbated stroke outcome and increased BBB impairment, transcriptional inactivation and inflammatory responses in females after stroke. Therefore, CaMKK signaling may be a potential target for stroke treatment in both males and females. The online version of this article (doi:10.1186/s12868-014-0118-2) contains supplementary material, which is available to authorized users.
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影响因子：
37.8
作者：
Go AS;Mozaffarian D;Roger VL;Benjamin EJ;Berry JD;Blaha MJ;Dai S;Ford ES;Fox CS;Franco S;Fullerton HJ;Gillespie C;Hailpern SM;Heit JA;Howard VJ;Huffman MD;Judd SE;Kissela BM;Kittner SJ;Lackland DT;Lichtman JH;Lisabeth LD;Mackey RH;Magid DJ;Marcus GM;Marelli A;Matchar DB;McGuire DK;Mohler ER 3rd;Moy CS;Mussolino ME;Neumar RW;Nichol G;Pandey DK;Paynter NP;Reeves MJ;Sorlie PD;Stein J;Towfighi A;Turan TN;Virani SS;Wong ND;Woo D;Turner MB;American Heart Association Statistics Committee and Stroke Statistics Subcommittee
通讯作者：
American Heart Association Statistics Committee and Stroke Statistics Subcommittee
影响因子：
5.3
作者：
Mizuno, Keiko;Ris, Laurence;Giese, K. Peter
通讯作者：
Giese, K. Peter
影响因子：
8.3
作者：
Fisher M;Feuerstein G;Howells DW;Hurn PD;Kent TA;Savitz SI;Lo EH;STAIR Group
通讯作者：
STAIR Group
影响因子：
5.3
作者：
Yuan, Mike;Siegel, Chad;Zeng, Zhiyuan;Li, Jun;Liu, Fudong;McCullough, Louise D.
通讯作者：
McCullough, Louise D.
影响因子：
8.3
作者：
Del Zoppo GJ;Saver JL;Jauch EC;Adams HP Jr;American Heart Association Stroke Council
通讯作者：
American Heart Association Stroke Council