Mongkolpathumrat Podsawee, Nernpermpisooth Nitirut, Kijtawornrat Anusak, Pikwong Faprathan, Chouyratchakarn Wannapat, Yodsheewan Rungrueang, Unajak Sasimanas, Kumphune Sarawut
Biomedical Engineering Institute (BMEI), Chiang Mai University, Chiang Mai, Thailand.
Integrative Biomedical Research Unit (IBRU), Faculty of Allied Health Sciences, Naresuan University, Phitsanulok, Thailand.
Front Cardiovasc Med. 2022 Aug 19;9:976083. doi: 10.3389/fcvm.2022.976083. eCollection 2022.
Protease enzymes contribute to the initiation of cardiac remodeling and heart failure after myocardial ischemic/reperfusion (I/R) injury. Protease inhibitors attenuate protease activity and limit left ventricular dysfunction and remodeling. Previous studies showed the cardioprotective effect of secretory leukocyte protease inhibitor (SLPI) against I/R injury. However, overexpression of SLPI gene in cardiovascular diseases has only been investigated in an experiment. Here, cardiac-selective expression of the human secretory leukocyte protease inhibitor (hSLPI) gene and its effect on I/R injury were investigated. Adeno-associated virus (AAV) serotype 9 carrying hSLPI under the control of cardiac-selective expression promoter (cardiac troponin, cTn) was intravenously administered to Sprague-Dawley rats for 4 weeks prior to coronary artery ligation. The results showed that myocardial-selective expression of hSLPI significantly reduced infarct size, cardiac troponin I (cTnI), creatine kinase-MB (CK-MB), and myoglobin levels that all served to improve cardiac function. Moreover, overexpression of hSLPI showed a reduction in inflammatory cytokines, oxidatively modified protein carbonyl (PC) content, ischemia-modified albumin (IMA), and necrosis and cardiac tissue degeneration. In conclusion, this is the first study to demonstrate cardiac-selective gene delivery of hSLPI providing cardioprotection against myocardial I/R injury in an model.
蛋白酶在心肌缺血/再灌注（I/R）损伤后引发心脏重塑和心力衰竭过程中发挥作用。蛋白酶抑制剂可减弱蛋白酶活性，限制左心室功能障碍和重塑。先前的研究表明分泌型白细胞蛋白酶抑制剂（SLPI）对I/R损伤具有心脏保护作用。然而，SLPI基因在心血管疾病中的过表达仅在一项实验中进行了研究。在此，研究了人类分泌型白细胞蛋白酶抑制剂（hSLPI）基因的心脏选择性表达及其对I/R损伤的影响。在冠状动脉结扎前4周，将携带在心脏选择性表达启动子（心肌肌钙蛋白，cTn）控制下的hSLPI的9型腺相关病毒（AAV）静脉注射给Sprague-Dawley大鼠。结果表明，hSLPI的心肌选择性表达显著减小了梗死面积，降低了心肌肌钙蛋白I（cTnI）、肌酸激酶同工酶MB（CK-MB）和肌红蛋白水平，所有这些都有助于改善心脏功能。此外，hSLPI的过表达显示炎症细胞因子、氧化修饰的蛋白质羰基（PC）含量、缺血修饰白蛋白（IMA）以及坏死和心脏组织变性均有所减少。总之，这是第一项证明hSLPI的心脏选择性基因递送在模型中对心肌I/R损伤提供心脏保护作用的研究。
