Department of Biomedical Sciences Joan C. Edwards School of Medicine at Marshall University Huntington WV USA.
Department of Pathophysiology College of Basic Medical Science, China Medical University Shenyang Liaoning China.
J Am Heart Assoc. 2023 Apr 4;12(7):e028023. doi: 10.1161/JAHA.122.028023. Epub 2023 Mar 28.
Background Ischemic cardiovascular disease is the leading cause of death worldwide. Current pharmacologic therapy has multiple limitations, and patients remain symptomatic despite maximal medical therapies. Deficiency or inhibition of thymidine phosphorylase (TYMP) in mice reduces thrombosis, suggesting that TYMP could be a novel therapeutic target for patients with acute myocardial infarction (AMI). Methods and Results A mouse AMI model was established by ligation of the left anterior descending coronary artery in C57BL/6J wild-type and TYMP-deficient () mice. Cardiac function was monitored by echocardiography or Langendorff assay. TYMP-deficient hearts had lower baseline contractility. However, cardiac function, systolic left ventricle anterior wall thickness, and diastolic wall strain were significantly greater 4 weeks after AMI compared with wild-type hearts. TYMP deficiency reduced microthrombus formation after AMI. TYMP deficiency did not affect angiogenesis in either normal or infarcted myocardium but increased arteriogenesis post-AMI. TYMP deficiency enhanced the mobilization of bone marrow stem cells and promoted mesenchymal stem cell (MSC) proliferation, migration, and resistance to inflammation and hypoxia. TYMP deficiency increased the number of larger MSCs and decreased matrix metalloproteinase-2 expression, resulting in a high homing capability. TYMP deficiency induced constitutive AKT phosphorylation in MSCs but reduced expression of genes associated with retinoid-interferon-induced mortality-19, a molecule that enhances cell death. Inhibition of TYMP with its selective inhibitor, tipiracil, phenocopied TYMP deficiency, improved post-AMI cardiac function and systolic left ventricle anterior wall thickness, attenuated diastolic stiffness, and reduced infarct size. Conclusions This study demonstrated that TYMP plays an adverse role after AMI. Targeting TYMP may be a novel therapy for patients with AMI.
背景 缺血性心血管疾病是全球范围内的主要致死原因。目前的药物治疗存在多种局限性，即使在接受最大程度的药物治疗后，患者仍会出现症状。在小鼠中，胸苷磷酸化酶（TYMP）的缺乏或抑制可减少血栓形成，这表明 TYMP 可能成为急性心肌梗死（AMI）患者的一个新的治疗靶点。
方法和结果 通过结扎 C57BL/6J 野生型和 TYMP 缺陷型（）小鼠的左前降支冠状动脉，建立了小鼠 AMI 模型。通过超声心动图或 Langendorff 测定法监测心脏功能。TYMP 缺陷型心脏的基础收缩力较低。然而，与野生型心脏相比，AMI 后 4 周，TYMP 缺陷型心脏的心脏功能、收缩期左心室前壁厚度和舒张期壁应变明显更大。TYMP 缺陷可减少 AMI 后的微血栓形成。TYMP 缺陷不影响正常或梗死心肌中的血管生成，但可增加 AMI 后的动脉生成。TYMP 缺陷增强了骨髓干细胞的动员，并促进了间充质干细胞（MSC）的增殖、迁移以及对炎症和缺氧的抵抗。TYMP 缺陷增加了较大 MSC 的数量，并降低了基质金属蛋白酶-2 的表达，从而提高了归巢能力。TYMP 缺陷诱导 MSC 中 AKT 的组成性磷酸化，但降低了与视黄醇-干扰素诱导的死亡率 19 相关的基因表达，该分子可增强细胞死亡。用其选择性抑制剂替吡嘧啶抑制 TYMP，可模拟 TYMP 缺陷，改善 AMI 后的心脏功能和收缩期左心室前壁厚度，减弱舒张期僵硬度，并减少梗死面积。
结论 本研究表明，TYMP 在 AMI 后发挥不利作用。靶向 TYMP 可能为 AMI 患者提供一种新的治疗方法。
