1] Medizinische Klinik und Poliklinik I, Klinikum Grosshadern, 81377 Munich, Germany [2] DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, 80802 München, Germany [3].
1] Medizinische Klinik und Poliklinik I, Klinikum Grosshadern, 81377 Munich, Germany [2] DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, 80802 München, Germany [3] Walter-Brendel-Centre of Experimental Medicine, Ludwig-Maximilians University, 81377 München, Germany [4].
Nat Commun. 2014 Jun 9;5:3970. doi: 10.1038/ncomms4970.
Gradual occlusion of coronary arteries may result in reversible loss of cardiomyocyte function (hibernating myocardium), which is amenable to therapeutic neovascularization. The role of myocardin-related transcription factors (MRTFs) co-activating serum response factor (SRF) in this process is largely unknown. Here we show that forced MRTF-A expression induces CCN1 and CCN2 to promote capillary proliferation and pericyte recruitment, respectively. We demonstrate that, upon G-actin binding, thymosin ß4 (Tß4), induces MRTF translocation to the nucleus, SRF-activation and CCN1/2 transcription. In a murine ischaemic hindlimb model, MRTF-A or Tß4 promotes neovascularization, whereas loss of MRTF-A/B or CCN1-function abrogates the Tß4 effect. We further show that, in ischaemic rabbit hindlimbs, MRTF-A as well as Tß4 induce functional neovascularization, and that this process is inhibited by angiopoietin-2, which antagonizes pericyte recruitment. Moreover, MRTF-A improves contractile function of chronic hibernating myocardium of pigs to a level comparable to that of transgenic pigs overexpressing Tß4 (Tß4tg). We conclude that MRTF-A promotes microvessel growth (via CCN1) and maturation (via CCN2), thereby enabling functional improvement of ischaemic muscle tissue.
冠状动脉的逐渐闭塞可能导致心肌细胞功能的可逆性丧失（冬眠心肌），这可通过治疗性新生血管化来改善。肌球蛋白相关转录因子（MRTFs）与血清反应因子（SRF）共同激活在这个过程中的作用在很大程度上是未知的。在这里，我们发现强制表达 MRTF-A 可诱导 CCN1 和 CCN2 的表达，分别促进毛细血管增殖和周细胞募集。我们证明，当 G-肌动蛋白结合时，胸腺素 β4（Tß4）诱导 MRTF 向核内易位，激活 SRF 和 CCN1/2 的转录。在小鼠缺血性后肢模型中，MRTF-A 或 Tß4 促进新生血管形成，而 MRTF-A/B 缺失或 CCN1 功能丧失则会削弱 Tß4 的作用。我们还发现，在缺血性兔后肢中，MRTF-A 和 Tß4 诱导功能性新生血管形成，而血管生成素-2 会抑制周细胞募集，从而抑制这一过程。此外，MRTF-A 可改善慢性冬眠心肌的收缩功能，使其达到过表达 Tß4（Tß4tg）的转基因猪的水平。我们的结论是，MRTF-A 可促进微血管生长（通过 CCN1）和成熟（通过 CCN2），从而改善缺血组织的功能。
