Chronic whole-body heat treatment relieves atherosclerotic lesions, cardiovascular and metabolic abnormalities, and enhances survival time restoring the anti-inflammatory and anti-senescent heat shock response in mice
Chronic whole-body heat treatment relieves atherosclerotic lesions, cardiovascular and metabolic abnormalities, and enhances survival time restoring the anti-inflammatory and anti-senescent heat shock response in mice
复制标题
DOI：
10.1016/j.biochi.2018.09.011
复制
发表时间：
2019-01-01
期刊：
影响因子：
3.9
通讯作者：
de Bittencourt Jr, Paulo Ivo Homem
中科院分区：
文献类型：
--
作者：
Bruxel, Maciel Alencar;Vicente Tavares, Angela Maria;de Bittencourt Jr, Paulo Ivo Homem
不健康的生活方式持续加剧代谢器官的炎症，从而产生衰老相关的分泌表型（SASP），正如在肥胖和 2 型糖尿病中观察到的那样。然而，SASP 通过抑制抗炎和抗衰老热休克 (HS) 反应（即以热休克因子 1 (HSF1) 依赖性表达热休克蛋白 (HSP) 为中心的基因程序）来阻止炎症的生理消退。由于 SASP 诱导因子未被消除，导致炎症持续存在，我们认为 SIRT1-HSF1-HSP 轴也可能在动脉粥样硬化中受到抑制，这可以通过热处理（HT）（最强大的 HS 反应触发因素）来逆转。 LDLr-/- 成年小鼠从90天龄开始一直喂食高脂肪/高胆固醇饮食，直到研究结束（270天龄）。在动脉粥样硬化饮食下 120 天后，动物在麻醉下接受全身 HT（n = 42；40 摄氏度）或假治疗（n = 59；37 摄氏度）治疗（15 分钟/次），每周一次，持续 8 周，并进行超声描记和代谢监测。与正常（LDLr+/+；n = 25）健康动物相比，动脉粥样硬化动物的主动脉 SIRT1、HSF1、HSP27、HSP72 和 HSP73 表达逐渐降低，同时 NF-κ B 依赖性 VCAM1 粘附分子表达增加。相反，HT 完全逆转了上述 HS 反应蛋白的抑制，同时显着抑制 VCAM1 表达和 NF-κ B DNA 结合活性。此外，HT 还显着降低了血浆中 TG、总胆固醇、低密度脂蛋白胆固醇、氧化应激、空腹血糖和胰岛素抵抗的水平，同时升高了高密度脂蛋白胆固醇水平。 HT 还可以减少体重增加、内脏脂肪、细胞浸润和主动脉脂肪条纹以及心室充血性肥大，从而改善主动脉血流量和心肌性能 (Tei) 指数。值得注意的是，经过热处理的小鼠在第三次 HT 疗程（相当于人类 8 年）后不再死亡，这表明有疗效。因此，动脉粥样硬化的演变与抗炎和抗衰老的SIRT1-HSF1-HSP分子轴的抑制有关，该分子轴通过长期热处理而得以更新。 (C) 2018 Elsevier B.V. 和法国 Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM)。版权所有。
Unhealthy lifestyle persistently feeds forward inflammation in metabolic organs thus imposing senescence-associated secretory phenotype (SASP), as observed in obesity and type 2 diabetes. However, SASP blocks physiological resolution of inflammation by suppressing the anti-inflammatory and anti-senescent heat shock (HS) response, i.e., the gene program centered in heat shock factor-1 (HSF1)-dependent expression heat shock proteins (HSPs). As SASP-inducing factors are not removed, leading to the perpetuation of inflammation, we argued that SIRT1-HSF1-HSP axis might also be suppressed in atherosclerosis, which could be reversible by heat treatment (HT), the most powerful HS response trigger. LDLr-/- adult mice were fed on high-fat/high-cholesterol diet from the age of 90 days until the end of study (age of 270 days). After 120 days under atherosclerotic diet, the animals were submitted to either whole-body HT (n = 42; 40 degrees C) or sham (n = 59; 37 degrees C) treatment (15 min/session), under anesthesia, once a week, for 8 weeks, being echographically and metabolically monitored. Aortic expressions of SIRT1, HSF1, HSP27, HSP72 and HSP73 were progressively depressed in atherosclerotic animals, as compared to normal (LDLr+/+; n = 25) healthy counterparts, which was paralleled by increased expression of NF-kappa B-dependent VCAM1 adhesion molecule. Conversely, HT completely reversed suppression of the above HS response proteins, while markedly inhibiting both VCAM1 expression and NF-kappa B DNA-binding activity. Also, HT dramatically reduced plasma levels of TG, total cholesterol, LDL-cholesterol, oxidative stress, fasting glucose and insulin resistance while rising HDL-cholesterol levels. HT also decreased body weight gain, visceral fat, cellular infiltration and aortic fatty streaks, and heart ventricular congestive hypertrophy, thereby improving aortic blood flow and myocardial performance (Tei) indices. Remarkably, heat-treated mice stopped dying after the third HT session (= 8 human years), suggesting a curative effect. Therefore, evolution of atherosclerosis is associated with suppression of the anti-inflammatory and anti-senescent SIRT1-HSF1-HSP molecular axis, which is refreshed by chronic heat treatment. (C) 2018 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved.