Metformin ameliorates gender-and age-dependent hemodynamic instability and myocardial injury in murine hemorrhagic shock.
Metformin ameliorates gender-and age-dependent hemodynamic instability and myocardial injury in murine hemorrhagic shock.
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DOI：
10.1016/j.bbadis.2017.05.027
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发表时间：
2017-10
期刊：
影响因子：
--
通讯作者：
Zingarelli B
中科院分区：
文献类型：
--
作者：
Matsiukevich D;Piraino G;Lahni P;Hake PW;Wolfe V;O'Connor M;James J;Zingarelli B
失血性休克患者的多器官衰竭严重程度受年龄和性别的显着影响。然而，器官损伤加剧的分子机制尚不完全清楚。 AMP 激活蛋白激酶 (AMPK) 是应激期间代谢反应的关键协调者。我们研究了出血引起的心肌损伤是否与年龄和性别相关，以及二甲双胍（一种 AMPK 激活剂）治疗是否具有心脏保护作用。对 C57/BL6 幼龄（3-5 个月）和成熟（9-12 个月）雄性和雌性小鼠进行失血性休克，然后用血液和乳酸林格氏液进行复苏。复苏后 3 小时，接受媒介物治疗的年轻和成熟小鼠的血浆炎症细胞因子水平相似。然而，根据超声心动图、组织学和心血管损伤生物标志物的评估，媒介物治疗的雄性成熟小鼠比年轻雄性小鼠经历了血流动力学不稳定和更高的心肌损伤。成熟组的心血管损伤也存在性别依赖性差异，因为媒介物治疗的雄性小鼠比雌性小鼠表现出更严重的器官损伤。在分子分析中，与年轻小鼠相比，经过媒介物治疗的两性成熟小鼠均表现出 AMPKα 激活和过氧化物酶体增殖物激活受体 γ 共激活剂 α 核易位的显着下调。二甲双胍治疗可改善雌雄成熟动物的心血管功能和存活率。然而，二甲双胍的具体心脏保护作用具有性别依赖性。二甲双胍不影响幼龄动物的血流动力学或炎症反应。因此，我们的数据表明，以二甲双胍为目标的代谢恢复可能是成人严重出血的潜在治疗方法。
Severity of multiple organ failure is significantly impacted by age and gender in patients with hemorrhagic shock. However, the molecular mechanisms underlying the enhanced organ injury are not fully understood. AMP-activated protein kinase (AMPK) is a pivotal orchestrator of metabolic responses during stress. We investigated whether hemorrhage-induced myocardial injury is age and gender dependent and whether treatment with metformin, an AMPK activator, affords cardioprotective effects. C57/BL6 young (3–5 months) and mature (9–12 months) male and female mice were subjected to hemorrhagic shock by blood withdrawing followed by resuscitation with blood and Lactated Ringer’s solution. Vehicle-treated young and mature mice of both genders had a similar elevation of plasma inflammatory cytokines at 3 hours after resuscitation. However, vehicle-treated male mature mice experienced hemodynamic instability and higher myocardial damage than young male mice, as evaluated by echocardiography, histology and cardiovascular injury biomarkers. There was also a gender-dependent difference in cardiovascular injury in the mature group as vehicle-treated male mice exhibited more severe organ injury than female mice. At molecular analysis, vehicle-treated mature mice of both genders exhibited a marked downregulation of AMPKα activation and nuclear translocation of peroxisome proliferator-activated receptor γ co-activator α when compared with young mice. Treatment with metformin improved cardiovascular function and survival in mature animals of both genders. However, specific cardioprotective effects of metformin were gender-dependent. Metformin did not affect hemodynamic or inflammatory responses in young animals. Thus, our data suggest that targeting metabolic recovery with metformin may be a potential treatment approach in severe hemorrhage in adult population.
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DOI：
10.1097/shk.0000000000000730
发表时间：
2017-01
期刊：
Shock (Augusta, Ga.)
影响因子：
--
作者：
Matsiukevich D;Piraino G;Klingbeil LR;Hake PW;Wolfe V;O'Connor M;Zingarelli B
通讯作者：
Zingarelli B
影响因子：
4.8
作者：
Judge, S;Jang, YM;Leeuwenburgh, C
通讯作者：
Leeuwenburgh, C
影响因子：
4.8
作者：
Acehan, Devrim;Vaz, Frederic;Khuchua, Zaza
通讯作者：
Khuchua, Zaza
影响因子：
3.7
作者：
Kristensen JM;Larsen S;Helge JW;Dela F;Wojtaszewski JF
通讯作者：
Wojtaszewski JF
DOI：
10.1073/pnas.0705070104
发表时间：
2007-07-17
影响因子：
11.1
作者：
Jaeger, Sibylle;Handschin, Christoph;Spiegelman, Bruce M.
通讯作者：
Spiegelman, Bruce M.