Jayasankar Vasant, Woo Y Joseph, Bish Lawrence T, Pirolli Timothy J, Chatterjee Subhasis, Berry Mark F, Burdick Jeffrey, Gardner Timothy J, Sweeney H Lee
Department of Cardiothoracic Surgery, University of Pennsylvania School of Medicine, Pliladelphia, PA 19104, USA.
Circulation. 2003 Sep 9;108 Suppl 1:II230-6. doi: 10.1161/01.cir.0000087444.53354.66.
Despite advances in surgical and percutaneous coronary revascularization, ongoing ischemia that is not amenable to standard revascularization techniques is a major cause of morbidity and mortality. Hepatocyte Growth Factor (HGF) has potent angiogenic and anti-apoptotic activities, and this study evaluated the functional and biochemical effects of HGF gene transfer in a rat model of postinfarction heart failure.
Lewis rats underwent ligation of the left anterior descending coronary artery with direct intramyocardial injection of replication-deficient recombinant adenovirus encoding HGF (n=10) or empty null virus as control (n=9), and animals were analyzed after six weeks. Pressure-volume conductance catheter measurements demonstrated significantly preserved contractile function in the HGF group compared with Null control animals as measured by maximum developed LV pressure (79+/-5 versus 56+/-4 mm Hg, P<0.001) and maximum dP/dt (2890+/-326 versus 1622+/-159 mm Hg/sec, P<0.01). Significant preservation of LV geometry was associated with HGF treatment (LV Diameter HGF 13.1+/-0.54 versus Null 14.4+/-0.15 mm P<0.01; LV wall thickness 1.73+/-0.10 versus 1.28+/-0.07 mm P<0.01). Angiogenesis was significantly enhanced in HGF treated animals as measured by both Von Willebrand's Factor immunohistochemical staining and a microsphere assay. TUNEL analysis revealed a significant reduction in apoptosis in the HGF group (3.42+/-0.83% versus 8.36+/-1.16%, P<0.01), which correlated with increased Bcl-2 and Bcl-xL expression in the HGF animals.
Hepatocyte Growth Factor gene transfer following a large myocardial infarction results in significantly preserved myocardial function and geometry, and is associated with significant angiogenesis and a reduction in apoptosis. This therapy may be useful as an adjunct or alternative to standard revascularization techniques in patients with ischemic heart failure.
尽管外科手术和经皮冠状动脉血运重建技术取得了进展，但对于标准血运重建技术难以解决的持续性缺血，仍是发病和死亡的主要原因。肝细胞生长因子（HGF）具有强大的血管生成和抗凋亡活性，本研究评估了HGF基因转移在心肌梗死后心力衰竭大鼠模型中的功能和生化作用。
将Lewis大鼠左冠状动脉前降支结扎，直接心肌内注射编码HGF的复制缺陷型重组腺病毒（n = 10）或空病毒作为对照（n = 9），六周后对动物进行分析。压力-容积导管测量显示，与空病毒对照组动物相比，HGF组的收缩功能显著保留，通过左心室最大压力（79±5对56±4 mmHg，P < 0.001）和最大dP/dt（2890±326对1622±159 mmHg/秒，P < 0.01）进行测量。HGF治疗与左心室几何形状的显著保留相关（左心室直径HGF组13.1±0.54对空病毒组14.4±0.15 mm，P < 0.01；左心室壁厚度1.73±0.10对1.28±0.07 mm，P < 0.01）。通过血管性血友病因子免疫组化染色和微球分析测量，HGF治疗动物的血管生成显著增强。TUNEL分析显示HGF组凋亡显著减少（3.42±0.83%对8.36±1.16%，P < 0.01），这与HGF动物中Bcl-2和Bcl-xL表达增加相关。
大面积心肌梗死后进行肝细胞生长因子基因转移可显著保留心肌功能和几何形状，并与显著的血管生成和凋亡减少相关。这种治疗方法可能作为缺血性心力衰竭患者标准血运重建技术的辅助或替代方法。
