Cao Sheng, Deng Qing, Wang Yijia, Zhou Yanxiang, Zhou Qing
Department of Ultrasound Imaging, Renmin Hospital of Wuhan University, Wuhan, China.
Ann Transl Med. 2021 Feb;9(3):221. doi: 10.21037/atm-20-839.
The present study aimed to determine whether ultrasound-targeted microbubble destruction (UTMD)-mediated angiopoietin 1 () gene transfection can improve angiogenesis and potentially reverse left ventricular (LV) structural and sympathetic nerve remodeling in canines with myocardial infarction (MI).
Thirty dogs were randomly divided into groups (n=10/group) as follows: the MI group (MI dogs without UTMD treatment), the UTMD group (MI dogs with UTMD-mediated negative control plasmid treatment), and the UTMD- group (MI dogs with UTMD-mediated plasmid treatment). LV dimensions, systolic function, and synchrony were used to reflect the structural remodeling. The density of tyrosine hydroxylase (TH)- and growth-associated protein 43 (GAP43)-positive nerve fibers were calculated to assess the sympathetic nerve remodeling.
One month after treatment, the UTMD- group showed lower LV end-diastolic dimension (LVEDD: 31.2±2.3 mm) and higher LV ejection fraction (LVEF: 44.6%±4.3%) than the MI group (LVEDD: 34.5±2.2 mm, t=2.282, P=0.014; LVEF: 37.3%±3.1%, t=3.718, P=0.003) and the UTMD group (LVEDD: 34.1±2.8 mm, t=2.264, P=0.040; LVEF: 39.3%±4.5%, t=2.408, P=0.030). LV synchrony was higher in the UTMD- group compared with the MI group by 2-dimensional speckle-tracking echocardiography. Angiogenic density was higher in the UTMD group than the MI group but was highest in the UTMD- group according to immunohistochemistry of CD31 and α-smooth muscle actin staining. The density of TH- and GAP43-positive nerve fibers were decreased in the UTMD- group (TH: 1,928.2±376.6 μm/mm; GAP43: 2,090.8±329.2 μm/mm) compared with the MI group (TH: 2916.5±558.4 μm/mm, t=4.069, P=0.001; GAP43: 3,275.4±548.6 μm/mm, t=5.153, P=0.000) and the UTMD group (TH: 2,552.7±408.1 μm/mm, t=3.181, P=0.007; GAP43: 2,630.5±419.3 μm/mm, t=2.863, P=0.013). The relative and sarcoplasmic reticulum Ca-ATPase 2a protein levels were significantly higher in the UTMD- group than the UTMD and MI groups by Western blot, while the phospholamban levels exhibited the opposite trend. Plasma norepinephrine and N-terminal pro-B-type-natriuretic peptide were significantly reduced in the UTMD- group from day 1 to 1 month after MI.
UTMD-mediated transfection can promote angiogenesis, reverse LV structural and sympathetic nerve remodeling, and improve LV synchrony after MI.
本研究旨在确定超声靶向微泡破坏（UTMD）介导的血管生成素1（）基因转染是否能改善血管生成，并可能逆转心肌梗死（MI）犬的左心室（LV）结构和交感神经重塑。
30只犬随机分为3组（每组n = 10）：MI组（未接受UTMD治疗的MI犬）、UTMD组（接受UTMD介导的阴性对照质粒治疗的MI犬）和UTMD-组（接受UTMD介导的质粒治疗的MI犬）。左心室尺寸、收缩功能和同步性用于反映结构重塑。计算酪氨酸羟化酶（TH）和生长相关蛋白43（GAP43）阳性神经纤维的密度以评估交感神经重塑。
治疗1个月后，UTMD-组的左心室舒张末期内径（LVEDD：31.2±2.3 mm）低于MI组（LVEDD：34.5±2.2 mm，t = 2.282，P = 0.014）和UTMD组（LVEDD：34.1±2.8 mm，t = 2.264，P = 0.040），左心室射血分数（LVEF：44.6%±4.3%）高于MI组（LVEF：37.3%±3.1%，t = 3.718，P = 0.003）和UTMD组（LVEF：39.3%±4.5%，t = 2.408，P = 0.030）。二维斑点追踪超声心动图显示，UTMD-组的左心室同步性高于MI组。根据CD31和α平滑肌肌动蛋白染色的免疫组织化学结果，UTMD组的血管生成密度高于MI组，但UTMD-组最高。与MI组（TH：2916.5±558.4 μm/mm，t = 4.069，P = 0.001；GAP43：3275.4±548.6 μm/mm，t = 5.153，P = 0.000）和UTMD组（TH：2552.7±408.1 μm/mm，t = 3.181，P = 0.007；GAP43：2630.5±419.3 μm/mm，t = 2.863，P = 0.013）相比，UTMD-组的TH和GAP43阳性神经纤维密度降低（TH：1928.2±376.6 μm/mm；GAP43：2090.8±329.2 μm/mm）。Western blot结果显示，UTMD-组的相对和肌浆网Ca-ATP酶2a蛋白水平显著高于UTMD组和MI组，而受磷蛋白水平则呈相反趋势。MI后1天至1个月，UTMD-组的血浆去甲肾上腺素和N末端B型利钠肽原显著降低。
UTMD介导的转染可促进血管生成，逆转MI后的左心室结构和交感神经重塑，并改善左心室同步性。
