Rangrez Ashraf Yusuf, Borlepawar Ankush, Schmiedel Nesrin, Deshpande Anushka, Remes Anca, Kumari Manju, Bernt Alexander, Christen Lynn, Helbig Andreas, Jungmann Andreas, Sossalla Samuel, Tholey Andreas, Müller Oliver J, Frank Derk, Frey Norbert
Department of Internal Medicine III (Cardiology, Angiology, Intensive Care), University Medical Center Kiel, Kiel, Germany.
DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Kiel, Germany.
Commun Biol. 2020 Oct 9;3(1):562. doi: 10.1038/s42003-020-01289-2.
Myocardial inflammation has recently been recognized as a distinct feature of cardiac hypertrophy and heart failure. HectD3, a HECT domain containing E3 ubiquitin ligase has previously been investigated in the host defense against infections as well as neuroinflammation; its cardiac function however is still unknown. Here we show that HectD3 simultaneously attenuates Calcineurin-NFAT driven cardiomyocyte hypertrophy and the pro-inflammatory actions of LPS/interferon-γ via its cardiac substrates SUMO2 and Stat1, respectively. AAV9-mediated overexpression of HectD3 in mice in vivo not only reduced cardiac SUMO2/Stat1 levels and pathological hypertrophy but also largely abolished macrophage infiltration and fibrosis induced by pressure overload. Taken together, we describe a novel cardioprotective mechanism involving the ubiquitin ligase HectD3, which links anti-hypertrophic and anti-inflammatory effects via dual regulation of SUMO2 and Stat1. In a broader perspective, these findings support the notion that cardiomyocyte growth and inflammation are more intertwined than previously anticipated.
心肌炎症最近被认为是心脏肥大和心力衰竭的一个显著特征。HectD3是一种含有HECT结构域的E3泛素连接酶，此前已在宿主抗感染防御以及神经炎症方面进行了研究；然而，其心脏功能仍然未知。在这里，我们表明，HectD3分别通过其心脏底物SUMO2和Stat1同时减弱钙调神经磷酸酶-NFAT驱动的心肌细胞肥大以及LPS/干扰素-γ的促炎作用。AAV9介导的HectD3在小鼠体内的过表达不仅降低了心脏SUMO2/Stat1水平和病理性肥大，而且在很大程度上消除了压力过载诱导的巨噬细胞浸润和纤维化。综上所述，我们描述了一种涉及泛素连接酶HectD3的新型心脏保护机制，该机制通过对SUMO2和Stat1的双重调节将抗肥大和抗炎作用联系起来。从更广泛的角度来看，这些发现支持了心肌细胞生长和炎症比以前预期的更加相互交织的观点。
