The E3 ubiquitin ligase HectD3 attenuates cardiac hypertrophy and inflammation in mice
Ashraf Yusuf Rangrez, Ankush Borlepawar, Nesrin Schmiedel, Anushka Deshpande, Anca Remes, Manju Kumari, Alexander Bernt, Lynn Christen, Andreas O. Helbig, Andreas Jungmann, Samuel Sossalla, Andreas Tholey, Oliver J. Müller, Derk Frank, Norbert Frey
Abstract
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.