PDF(Pubmed)
Abstract：
Maladaptive cardiac hypertrophy contributes to the development of heart failure (HF). The oxidoreductase Selenoprotein T (SELENOT) emerged as a key regulator during rat cardiogenesis and acute cardiac protection. However, its action in chronic settings of cardiac dysfunction is not understood. Here, we investigated the role of SELENOT in the pathophysiology of HF: (i) by designing a small peptide (PSELT), recapitulating SELENOT activity via the redox site, and assessed its beneficial action in a preclinical model of HF [aged spontaneously hypertensive heart failure (SHHF) rats] and against isoproterenol (ISO)-induced hypertrophy in rat ventricular H9c2 and adult human AC16 cardiomyocytes; (ii) by evaluating the SELENOT intra-cardiomyocyte production and secretion under hypertrophied stimulation. Results showed that PSELT attenuated systemic inflammation, lipopolysaccharide (LPS)-induced macrophage M1 polarization, myocardial injury, and the severe ultrastructural alterations, while counteracting key mediators of cardiac fibrosis, aging, and DNA damage and restoring desmin downregulation and SELENOT upregulation in the failing hearts. In the hemodynamic assessment, PSELT improved the contractile impairment at baseline and following ischemia/reperfusion injury, and reduced infarct size in normal and failing hearts. At cellular level, PSELT counteracted ISO-mediated hypertrophy and ultrastructural alterations through its redox motif, while mitigating ISO-triggered SELENOT intracellular production and secretion, a phenomenon that presumably reflects the extent of cell damage. Altogether, these results indicate that SELENOT could represent a novel sensor of hypertrophied cardiomyocytes and a potential PSELT-based new therapeutic approach in myocardial hypertrophy and HF.
摘要：
适应不良的心脏肥大有助于心力衰竭（HF）的发展。氧化还原酶硒蛋白T（SELENOT）是大鼠心脏发生和急性心脏保护过程中的关键调节剂。然而,其在慢性心功能不全中的作用尚不清楚。这里,我们研究了SELENOT在HF病理生理学中的作用：（i）通过设计小肽（PSELT），通过氧化还原位点概括SELENOT活性，并评估了其在HF[老年自发性高血压心力衰竭（SHHF）大鼠]的临床前模型中的有益作用，以及对异丙肾上腺素（ISO）诱导的大鼠心室H9c2和成人AC16心肌细胞的肥大的有益作用；（ii）通过评估SELENOT在肥大刺激下心肌细胞内的产生和分泌。结果显示，PSELT可以减轻全身炎症，脂多糖（LPS）诱导的巨噬细胞M1极化，心肌损伤，以及严重的超微结构改变，同时抵消心脏纤维化的关键介质，老化，在衰竭的心脏中，DNA损伤并恢复结蛋白下调和SELENOT上调。在血液动力学评估中，PSELT改善了基线和缺血/再灌注损伤后的收缩损伤，并减少正常心脏和衰竭心脏的梗死面积。在细胞水平，PSELT通过其氧化还原基序抵消了ISO介导的肥大和超微结构改变，在减轻ISO触发的SELENOT细胞内产生和分泌的同时，一种可能反映细胞损伤程度的现象。总之,这些结果表明,SELENOT可以代表肥大心肌细胞的新型传感器和基于PSELT的心肌肥大和HF的潜在新治疗方法.
