延髓头端腹外侧区衰老细胞参与老年血压稳态失衡的机制研究

Aging of population is a grim social problem in our country. Therefore, it is particularly necessary to investigate the molecular mechanism that leads to the disrupted homeostasis of blood pressure caused by aging and explore the effective prevention and therapy strategies. With this in mind, baroreflex sensitivity and plasma TMAO levels in healthy subjects of different ages is determined to investigate the correlation between them. And then, the aged rat is used to confirm that decreased baroreflex sensitivity and disrupted blood pressure homeostasis are associated with increased TMAO levels. Patch clamp, cell culture, molecular biology techniques, etc. are used to clear that the increased TMAO levels induce the decrease of SIRT1 activity, which promotes senescence and initiates senescence-associated secretory shenotype (SASP) of neuronal cells in RVLM and the senescent cells may be involved in the central inflammation of RVLM in the aged rats，which leads to excessive activation of sympathetic nerves, decrease baroreflex sensitivity and disrupt blood pressure homeostasis. However，H2S may reduce central inflammation by increasing neuronal SIRT1 activity, then increase baroreflex sensitivity and maintain blood pressure homeostasis in the aged rats. Microscale thermophoresis, Biacore, XAFS and other spectroscopy methods are used to explore whether H2S binds directly to the zinc ion of the SIRT1 active center to directly increase its activity. This will shed light on the neurological and molecular mechanisms of disrupted blood pressure homeostasis caused by aging and provide theoretical bases for its prevention and therapy.

人口老龄化是我国面临的一个非常严峻的社会问题。探讨衰老所致的血压稳态失衡的发生机制，寻找有效防治措施尤为必要。本项目通过检测不同年龄健康受试者压力感受性反射敏感性与血浆TMAO水平的相关性，并在衰老大鼠上明确压力感受性反射钝化及血压稳态失衡与TMAO水平增高有关。应用脑片膜片钳、细胞培养、分子生物学技术等，明确TMAO含量增高诱发SIRT1活性下降进而引起RVLM区神经元细胞衰老及衰老细胞分泌表型转化可能参与了衰老大鼠RVLM区的中枢炎症反应，从而导致交感神经过度激活，压力感受性反射钝化，引起血压稳态失衡；H2S可能通过提高神经元SIRT1活性减低中枢炎症，敏化衰老大鼠压力感受性反射，维持血压稳态。应用微量热泳动仪、Biacore、XAFS等多种光谱学方法探讨H2S是否与SIRT1活性中心的锌离子结合来直接提高其活性，从而揭示衰老所致血压稳态失衡发生的神经和分子机制，为其防治提供理论依据。

人口老龄化是我国面临的一个非常严峻的社会问题，衰老相关的血压调节异常、血压稳态失衡严重威胁着老年人生命安全，影响着老年人的生活质量，因此对其发生机制及有效防治措施的探讨尤为必要。本项目拟从整体、组织、细胞、蛋白和分子水平探讨RVLM区衰老细胞介导的中枢炎症在老年压力感受性反射钝化所致的血压稳态失衡中的具体机制，并进一步观察增龄所致的TMAO水平升高是否与RVLM区细胞衰老有关，而H2S是否通过提高SIRT1活性减轻TMAO所致的细胞衰老，进而调节RVLM区炎症因子水平，抑制交感神经系统的过度激活，缓解衰老所致的压力感受性反射钝化，从而维持血压的稳态。我们研究发现不同年龄的健康体检者随着年龄的增长血压逐渐增加，同时血浆中TMAO及去甲肾上腺素水平明显增加，而H2S水平明显降低。随后在衰老大鼠上进行验证发现，与年轻对照大鼠相比，衰老大鼠压力感受性反射钝化，肾神经放电明显增多，同时血浆中TMAO含量明显增加，而H2S水平明显降低。进而我们给予大鼠喂食含1.2%胆碱的饲料，发现大鼠血浆和RVLM区TMAO含量均明显升高，交感神经紧张性进一步增强，压力感受性反射钝化，同时RVLM区TNF-α和IL-1β含量明显增加。为了证明TMAO能够直接引起交感神经过度激活，我们侧脑室注射TMAO，发现其可使麻醉大鼠的血压显著升高，心率加快，肾神经放电明显增多，同时RVLM区TNF-α、IL-1β含量明显增多，SIRT1活性明显下降。外源性给予NaHS（H2S供体）可以明显提高SIRT1活性，降低TMAO引起的血压升高，心率加快，肾神经放电增多，以及RVLM区TNF-α和IL-1β的含量。从而证实H2S可通过提高SIRT1活性抑制RVLM区炎症而改善TMAO引起的交感神经过度激活。通过上述研究可以揭示衰老所致血压稳态失衡发生的神经和分子机制，为其防治提供理论依据。

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