IGFBP-4作为阻止心肌缺血损伤药物可能性的探索研究

Acute myocardial infarction (MI) and lower limb ischemia are common acute ischemic disease. In particular, acute MI is one of the leading causes of mortality in the world, with a high incidence rate and poor disease prognosis. DNA damage is the earliest response system which occurs following ischemic and hypoxic injury. Severe DNA damage can directly lead to widespread cell death, and is a key mechanism in the occurrence of acute ischemic damage. Our preliminary studies have found that Wnt signaling pathway inhibitor IGFBP-4 plays a crucial role in protecting the myocardium and lower limb muscle from ischemic injury, and that this protection is due to the prevention of early stage DNA damage. We understand the current clinical treatment of acute ischemia is through promoting neovascularization in the ischemic tissue. However, due to the lengthy duration required for the formation of new blood vessels, this cannot prevent early stage DNA damage, resulting in a lowered efficacy of treatment. Therefore, we intend to utilize the advantages of pro-angiogenic factor VEGF, in combination with IGFBP-4, to further evaluate the cardioprotective, cardioregenerative and vasoregenerative effects following acute MI and lower limb ischemia. This applicant has previously discovered a separate secreted protein G-CSF, which can prevent ischemic myocardium death following myocardial ischemia. G-CSF has now been widely in use clinically for the treatment of patients with acute MI and stroke, due to its cardioprotective and subsequently discovered neuroprotective effects. Therefore, in our present study, we intend to compare the effect of G-CSF with IGFBP-4 treatment on acute MI and lower limb ischemia, in order to further highlight the protective effect of IGFBP-4. Through these studies, we hope to provide a solid foundation for the development of IGFBP-4 as a drug for the clinical treatment of ischemic diseases.

急性心肌缺血是常见的急性缺血性疾病。DNA损伤是缺血后最早发生的损伤反应，严重的DNA损伤会直接导致细胞死亡，是急性缺血性疾病损伤发生的重要机制。我们的前期研究发现Wnt信号通路抑制因子IGFBP-4具有保护心肌缺血损伤的作用，并且这种作用是通过阻止DNA损伤而发生的。我们知道促进缺血部位新生血管形成重建血管通路是一个常用的传统治疗方案，但由于新生血管形成需要时程长，无法阻止早期的DNA损伤，疗效欠佳。因此，我们拟利用促血管新生因子VEGF与IGFBP-4联合用药，进一步观察两者对急性缺血的保护作用。申请者以前发现分泌蛋白G-CSF可以通过阻止心肌细胞死而保护缺血对心肌的损伤。因此，我们也拟比较G-CSF与IGFBP-4对这些缺血损伤的保护作用的效果，从而进一步明确IGFBP-4的缺血保护效应。通过上述研究，必将为开发IGFBP-4治疗急性缺血性疾病药物提供坚实的依据。

急性心肌缺血是常见的急性缺血性疾病。DNA损伤是缺血后最早发生的损伤反应，严重的DNA损伤会直接导致细胞死亡，是急性缺血性疾病损伤发生的重要机制。我们的前期研究发现Wnt信号通路抑制因子IGFBP-4具有保护心肌缺血损伤的作用，并且这种作用是通过阻止DNA损伤而发生的。促进缺血部位新生血管形成重建血管通路是一个常用的传统治疗方案，但由于新生血管形成需要时程长，无法阻止早期的DNA损伤，疗效欠佳。因此，本研究通过体外、体内实验证实IGFBP-4对急性缺血的保护作用及其机制，为开发IGFBP-4治疗急性缺血性疾病药物提供坚实的依据。