RhoA/ROCK信号通路在心衰大鼠心脏铁代谢紊乱中的作用机制的研究

iron plays a crucial role in cellular function in general and oxidative metabolism in particular, especially in metabolically active tissue，such as heart. Iron de?ciency, as well as iron overload, might lead to myocardial dysfunction and heart failure. Body iron deficiency is known to be common in patients with heart failure, however, iron change in heart is still needed to be determined. Our results suggest iron in heart tissue is decreased by adriamycin while that is reversed by fasudil. Based on our previous studies, we would like to continue our study at the whole animal, cellular, and molecular levels as following: 1. To confirm disturbed iron metabolism in the hearts of the heart failure rats; 2. To explore the possible signaling crosstalk between ROCK and hepcidin during heart failure in rats; 3. To study the molecular mechanism about how heart iron homeostasis is regulated by hepcidin in heart failure rats.

铁在机体正常代谢过程中起着至关重要的作用，尤其是在心脏这一能量代谢旺盛的器官，无论铁增加还是减少均会引起心衰。尽管有大量证据表明心衰患者机体铁缺乏，但是关于心衰患者心脏组织铁的变化到底是增加还是减少还需要进一步确认。根据我们已有的结果表明，Adr引起的心衰大鼠心肌组织铁减少，fasudil处理后，心肌组织铁增加。为此，本课题拟在我们前期的研究基础上，运用透射电镜、组织学及分子生物学等技术，从整体动物、细胞和分子水平，系统研究1.心衰状态下心脏铁代谢的改变；2.心衰状态下心脏hepcidin的表达变化与RhoA/ROCK信号通路相互作用；3.hepcidin调控心衰大鼠心脏铁代谢稳态的分子机制。目的在于揭示RhoA/ROCK信号通路在心衰大鼠心脏铁代谢紊乱中的作用机制，明确fasudil通过抑制ROCK降低hepcidin表达，减少细胞凋亡，改善心衰的机制，为防治心衰提供新的思路。

铁在机体正常代谢过程中起着至关重要的作用，尤其是在心脏这一能量代谢旺盛的器官，无论铁增加还是减少均会引起心衰。本研究发现，阿霉素诱导心衰模型大鼠血清铁含量增加而采用腹主动脉缩窄术复制的心衰模型大鼠血清铁含量减少，推测可能是阿霉素对肝脏的毒副作用导致血清铁的变化与临床结果不一致，所以后续试验采用腹主动脉缩窄术复制的心衰模型大鼠。Fasudil干预后，大鼠心衰得到缓解并且心肌组织铁含量增加。检测发现，法舒地尔干预引起了血清铁和心肌组织铁含量增加，肝脏hepcidin表达降低、细胞核内SMAD4减少，十二指肠Ferroportin表达增多，心肌组织TfR1和DMT1表达增多。RhoA/ROCK信号通路调节心肌铁代谢的机制可能有两方面：一是RhoA/ROCK信号通路被法舒地尔抑制后减少肝脏SMAD4入核，进而引起的hepcidin下调，造成机体铁摄取增加，增加了整体的铁供给；二是抑制RhoA/ROCK信号通路后，增加了IRP/IRE的结合活性，引起心肌TfR1和DMT1表达增加，心肌自身铁摄取能力增强。本研究揭示了RhoA/ROCK信号通路参与调节心衰大鼠心脏铁代谢稳态的作用机制，为防治心衰提供新的思路。