Iwanaga Yoshitaka, Hoshijima Masahiko, Gu Yusu, Iwatate Mitsuo, Dieterle Thomas, Ikeda Yasuhiro, Date Moto-o, Chrast Jacqueline, Matsuzaki Masunori, Peterson Kirk L, Chien Kenneth R, Ross John
Department of Medicine, University of California, San Diego, La Jolla, California 92093-0613B, USA.
J Clin Invest. 2004 Mar;113(5):727-36. doi: 10.1172/JCI18716.
Ablation or inhibition of phospholamban (PLN) has favorable effects in several genetic murine dilated cardiomyopathies, and we showed previously that a pseudophosphorylated form of PLN mutant (S16EPLN) successfully prevented progressive heart failure in cardiomyopathic hamsters. In this study, the effects of PLN inhibition were examined in rats with heart failure after myocardial infarction (MI), a model of acquired disease. S16EPLN was delivered into failing hearts 5 weeks after MI by transcoronary gene transfer using a recombinant adeno-associated virus (rAAV) vector. In treated (MI-S16EPLN, n = 16) and control (MI-saline, n = 18) groups, infarct sizes were closely matched and the left ventricle was similarly depressed and dilated before gene transfer. At 2 and 6 months after gene transfer, MI-S16EPLN rats showed an increase in left ventricular (LV) ejection fraction and a much smaller rise in LV end-diastolic volume, compared with progressive deterioration of LV size and function in MI-saline rats. Hemodynamic measurements at 6 months showed lower LV end-diastolic pressures, with enhanced LV function (contractility and relaxation), lowered LV mass and myocyte size, and less fibrosis in MI-S16EPLN rats. Thus, PLN inhibition by in vivo rAAV gene transfer is an effective strategy for the chronic treatment of an acquired form of established heart failure.
消融或抑制受磷蛋白（PLN）在几种遗传性小鼠扩张型心肌病中具有有益作用，并且我们之前表明PLN突变体的假磷酸化形式（S16EPLN）成功预防了心肌病仓鼠的进行性心力衰竭。在本研究中，在心肌梗死（MI）后发生心力衰竭的大鼠（一种获得性疾病模型）中检测了PLN抑制的作用。通过使用重组腺相关病毒（rAAV）载体经冠状动脉基因转移，在MI后5周将S16EPLN递送至衰竭心脏。在治疗组（MI-S16EPLN，n = 16）和对照组（MI-盐水，n = 18）中，梗死面积紧密匹配，并且在基因转移前左心室同样地收缩和扩张。在基因转移后2个月和6个月时，与MI-盐水组大鼠左心室大小和功能的进行性恶化相比，MI-S16EPLN大鼠左心室（LV）射血分数增加，左心室舒张末期容积增加幅度小得多。6个月时的血流动力学测量显示MI-S16EPLN大鼠左心室舒张末期压力较低，左心室功能（收缩性和舒张性）增强，左心室质量和心肌细胞大小降低，纤维化减少。因此，通过体内rAAV基因转移抑制PLN是慢性治疗已确诊的获得性心力衰竭的有效策略。
