Klinik und Poliklinik Innere Medizin I, Klinikum rechts der Isar - Technical University of Munich, 81675 Munich, Germany; DZHK (German Centre for Cardiovascular Research) - partner site Munich Heart Alliance, 81675 Munich, Germany.
Klinik und Poliklinik Innere Medizin I, Klinikum rechts der Isar - Technical University of Munich, 81675 Munich, Germany.
Mol Ther. 2018 Jul 5;26(7):1706-1714. doi: 10.1016/j.ymthe.2018.06.004. Epub 2018 Jun 19.
Translations of new therapeutic options for cardiovascular disease from animal studies into a clinical setting have been hampered, in part by an improper reflection of a relevant patient population in animal models. In this study, we investigated the impact of thymosin β4 (Tβ4), which promotes collateralization and capillarization, during hypercholesterolemia, a known risk factor of coronary artery disease. Initial in vitro results highlighted an improved endothelial cell function upon Tβ4 treatment under control conditions and during hypercholesterolemic stress (scratch area [pixels]: oxidized low-density lipoprotein [oxLDL], 191,924 ± 7,717; and oxLDL + Tβ4, 105,621 ± 11,245). To mimic the common risk factor of hypercholesterolemia in vivo, pigs on regular (NC) or high-fat (HC) diet underwent chronic myocardial ischemia followed by recombinant adeno-associated virus (rAAV)-mediated transduction of Tβ4 or LacZ as a control. We show that Tβ4 overexpression improves capillarization and collateralization (collaterals: NC + rAAV.LacZ, 2.1 ± 0.5; NC + rAAV.Tβ4, 6.7 ± 0.5; HC + rAAV.LacZ, 3.0 ± 0.3; and HC + rAAV.Tβ4, 6.0 ± 0.4), ultimately leading to an improved myocardial function in both diet groups (ejection fraction [EF] at day 56 [%]: NC + rAAV.LacZ, 26 ± 1.1; NC + rAAV.Tβ4, 45 ± 1.5; HC + rAAV.LacZ, 26 ± 2.5; and HC + rAAV.Tβ4, 41 ± 2.6). These results demonstrate the potency of Tβ4 in a patient-relevant large animal model of chronic myocardial ischemia.
从动物研究到临床应用，心血管疾病新治疗选择的转化一直受到阻碍，部分原因是动物模型中未能正确反映相关患者人群。在这项研究中，我们研究了胸腺肽β4（Tβ4）的影响，Tβ4 可促进侧支血管形成和毛细血管生成，而高胆固醇血症是冠状动脉疾病的已知危险因素。最初的体外结果表明，在对照条件和高胆固醇血症应激下（划痕面积[像素]：氧化型低密度脂蛋白[oxLDL]，191924±7717；和 oxLDL+Tβ4，105621±11245），Tβ4 处理可改善内皮细胞功能。为了模拟体内高胆固醇血症的常见危险因素，接受常规（NC）或高脂肪（HC）饮食的猪经历了慢性心肌缺血，随后接受重组腺相关病毒（rAAV）介导的 Tβ4 或 LacZ 转导作为对照。我们表明，Tβ4 过表达可改善毛细血管生成和侧支血管形成（侧支血管：NC+rAAV.LacZ，2.1±0.5；NC+rAAV.Tβ4，6.7±0.5；HC+rAAV.LacZ，3.0±0.3；和 HC+rAAV.Tβ4，6.0±0.4），最终导致两组饮食的心肌功能得到改善（第 56 天射血分数[EF] [%]：NC+rAAV.LacZ，26±1.1；NC+rAAV.Tβ4，45±1.5；HC+rAAV.LacZ，26±2.5；和 HC+rAAV.Tβ4，41±2.6）。这些结果表明，Tβ4 在慢性心肌缺血的患者相关大型动物模型中具有强大的作用。
