Abstract：
Uncorrected obesity is accompanied by unfavorable structural and functional changes in the heart, known as obesity cardiomyopathy. Recent evidence has revealed a crucial role for mitochondria-associated endoplasmic reticulum membranes (MAMs) in obesity-induced cardiac complication. Syntaxin 17 (STX17) serves as a scaffolding molecule localized on MAMs although its role in obesity heart complication remains elusive.
This study examined the role of STX17 in MAMs and mitochondrial Ca2+ homeostasis in HFD-induced obesity cardiomyopathy using tamoxifen-induced cardiac-specific STX17 knockout (STX17cko) and STX17 overexpression mice using intravenously delivered recombinant adeno-associated virus serotype-9 (AAV9-cTNT-STX17).
STX17 levels were significantly elevated in plasma from obese patients and heart tissues of HFD-fed mice. Our data revealed that cardiac STX17 knockout alleviated cardiac remodeling and dysfunction in obese hearts without eliciting any notable effect itself, while STX17 overexpression aggravated cardiac dysfunction in obese mice. STX17 deletion and STX17 overexpression annihilated and aggravated, respectively, HFD-induced oxidative stress (O2- production) and mitochondrial injury in the heart. Furthermore, STX17 transfection facilitated obesity-induced MAMs formation in cardiomyocytes and evoked excess mitochondrial Ca2+ influx, dependent upon interaction with mitochondrial Ca2+ uniporter dominant negative β (MCUb) through Habc domain. Our data also suggested that STX17 promoted ubiquitination and degradation of MCUb through the E3 ligase parkin in the face of palmitate challenging.
Taken together, our results identified a novel role for STX17 in facilitating obesity-induced MAMs formation, and subsequently mitochondrial Ca2+ overload, mitochondrial O2- accumulation, lipid peroxidation, resulting in cardiac impairment. Our findings denoted therapeutic promises of targeting STX17 in obesity.
This study examined the role of STX17 in MAMs and mitochondrial Ca2+ homeostasis in HFD-induced obesity cardiomyopathy using tamoxifen-induced cardiac-specific STX17 knockout (STX17cko) and STX17 overexpression mice using intravenously delivered recombinant adeno-associated virus serotype-9 (AAV9-cTNT-STX17).
STX17 levels were significantly elevated in plasma from obese patients and heart tissues of HFD-fed mice. Our data revealed that cardiac STX17 knockout alleviated cardiac remodeling and dysfunction in obese hearts without eliciting any notable effect itself, while STX17 overexpression aggravated cardiac dysfunction in obese mice. STX17 deletion and STX17 overexpression annihilated and aggravated, respectively, HFD-induced oxidative stress (O2- production) and mitochondrial injury in the heart. Furthermore, STX17 transfection facilitated obesity-induced MAMs formation in cardiomyocytes and evoked excess mitochondrial Ca2+ influx, dependent upon interaction with mitochondrial Ca2+ uniporter dominant negative β (MCUb) through Habc domain. Our data also suggested that STX17 promoted ubiquitination and degradation of MCUb through the E3 ligase parkin in the face of palmitate challenging.
Taken together, our results identified a novel role for STX17 in facilitating obesity-induced MAMs formation, and subsequently mitochondrial Ca2+ overload, mitochondrial O2- accumulation, lipid peroxidation, resulting in cardiac impairment. Our findings denoted therapeutic promises of targeting STX17 in obesity.
摘要：
目的：未矫正的肥胖伴随着心脏不利的结构和功能变化，被称为肥胖心肌病。最近的证据表明，线粒体相关的内质网膜（MAMs）在肥胖引起的心脏并发症中起着至关重要的作用。Syntaxin17（STX17）充当位于MAM上的支架分子，尽管其在肥胖心脏并发症中的作用仍然难以捉摸。
方法：本研究使用他莫昔芬诱导的心脏特异性STX17基因敲除（STX17cko）和使用静脉注射重组腺相关病毒血清型9（AAV9-cTNT-STX17）的STX17过表达小鼠，研究了STX17在HFD诱导的肥胖心肌病中的MAMs和线粒体Ca2+稳态中的作用。
结果：STX17水平在肥胖患者的血浆和HFD喂养小鼠的心脏组织中显著升高。我们的数据显示，心脏STX17基因敲除减轻了肥胖心脏的心脏重塑和功能障碍，本身没有引起任何显著的影响。而STX17过表达加重了肥胖小鼠的心功能障碍。STX17缺失和STX17过表达消失和加剧，分别,HFD诱导的心脏氧化应激(O2-产生)和线粒体损伤。此外，STX17转染促进肥胖诱导的心肌细胞MAMs的形成，并引起过量的线粒体Ca2+流入，依赖于通过Habc结构域与线粒体Ca2+单转体显性阴性β(MCUb)的相互作用。我们的数据还表明，面对棕榈酸酯的挑战，STX17通过E3连接酶parkin促进了MCUb的泛素化和降解。
结论：综合来看，我们的结果确定了STX17在促进肥胖诱导的MAMs形成中的新作用，随后线粒体Ca2+过载，线粒体O2积累，脂质过氧化，导致心脏损伤。我们的发现表明了在肥胖中靶向STX17的治疗前景。
方法：本研究使用他莫昔芬诱导的心脏特异性STX17基因敲除（STX17cko）和使用静脉注射重组腺相关病毒血清型9（AAV9-cTNT-STX17）的STX17过表达小鼠，研究了STX17在HFD诱导的肥胖心肌病中的MAMs和线粒体Ca2+稳态中的作用。
结果：STX17水平在肥胖患者的血浆和HFD喂养小鼠的心脏组织中显著升高。我们的数据显示，心脏STX17基因敲除减轻了肥胖心脏的心脏重塑和功能障碍，本身没有引起任何显著的影响。而STX17过表达加重了肥胖小鼠的心功能障碍。STX17缺失和STX17过表达消失和加剧，分别,HFD诱导的心脏氧化应激(O2-产生)和线粒体损伤。此外，STX17转染促进肥胖诱导的心肌细胞MAMs的形成，并引起过量的线粒体Ca2+流入，依赖于通过Habc结构域与线粒体Ca2+单转体显性阴性β(MCUb)的相互作用。我们的数据还表明，面对棕榈酸酯的挑战，STX17通过E3连接酶parkin促进了MCUb的泛素化和降解。
结论：综合来看，我们的结果确定了STX17在促进肥胖诱导的MAMs形成中的新作用，随后线粒体Ca2+过载，线粒体O2积累，脂质过氧化，导致心脏损伤。我们的发现表明了在肥胖中靶向STX17的治疗前景。
