Sirtuin 4通过增强活性氧介导的纤维化转录信号加速心力衰竭的发展

Nikole J. Byrne , Christoph Koentges , Elisabeth Khan , Katharina Pfeil , Robert Sandulescu , Sayan Bakshi , Carolin Költgen , Ivan Vosko , Johannes Gollmer , Thomas Rathner , Günter Roth , Michael M. Hoffmann , Katja E. Odening , Hauke Horstmann , Luke A. Potter , Christoph Bode , Dennis Wolf , Harald Sourij , Senka Ljubojevic-Holzer , Markus Wallner , Heiko Bugger
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引用次数: 0

摘要

aimsirtuin 4 (SIRT4)是线粒体定位的应激反应性NAD+依赖的去乙酰化酶,主要调节能量代谢和活性氧(ROS)稳态。SIRT4的过表达加重了血管紧张素诱导的心肌肥厚,但其潜在机制尚未完全阐明。目前的研究旨在探索压力过载后心脏中SIRT4水平升高的不良影响机制。方法和结果心肌细胞特异性过表达Sirt4 (cSirt4-Tg)或非转基因对照者行主动脉横缩术(TAC)或假手术。通过超声心动图和工作灌注评估心脏结构、功能和能量代谢。使用RNA测序进行转录组分析。在TAC后9周及之后,与非转基因对照组相比,cSirt4-Tg小鼠表现出心脏扩张、功能障碍和纤维化加剧。这种加重伴随着糖酵解率受损和线粒体呼吸能力的钝化增加。更重要的是,许多编码胶原蛋白和促纤维化调节因子的基因表达升高。使用MitoQ进行线粒体靶向抗氧化治疗可以逆转这种纤维化信号,同时减弱心功能障碍和逆转结构重塑。SIRT4可能通过增加NOX4表达(>;7倍)和/或直接调节人类蛋白微阵列新发现的潜在SIRT4靶点,包括降钙素基因相关肽受体成分蛋白、亲环蛋白A和白素-2受体β,来驱动氧化应激和纤维化信号传导。结论sirt4过表达加速心力衰竭的发展,主要是通过ros介导的促纤维化转录信号的增强来响应压力过载。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Sirtuin 4 accelerates heart failure development by enhancing reactive oxygen species-mediated profibrotic transcriptional signaling

Sirtuin 4 accelerates heart failure development by enhancing reactive oxygen species-mediated profibrotic transcriptional signaling

Aims

Sirtuin 4 (SIRT4) is a mitochondrially-localized stress-responsive NAD+-dependent deacetylase predominantly regulating energy metabolism and reactive oxygen species (ROS) homeostasis. Overexpression of SIRT4 aggravates angiotensin-induced cardiac hypertrophy, however underlying mechanisms remain incompletely elucidated. To current study was designed to explore mechanisms underlying adverse effects of increased SIRT4 levels in the heart following pressure overload.

Methods and results

Mice with cardiomyocyte-specific overexpression of Sirt4 (cSirt4-Tg) or non-transgenic controls underwent transverse aortic constriction (TAC) or sham procedure. Cardiac structure, function and energy metabolism were assessed by echocardiography and working heart perfusions. Transcriptome analysis was performed using RNA sequencing. Nine weeks following TAC and thereafter, cSirt4-Tg mice displayed exacerbated cardiac dilation, dysfunction, and fibrosis compared to non-transgenic controls. This aggravation was accompanied by impaired rates of glycolysis and a blunted increase of mitochondrial respiratory capacity. More importantly, expression of numerous genes encoding collagens and profibrotic regulators was elevated. This profibrotic signaling was reversed by mitochondria-targeted antioxidant treatment using MitoQ, along with attenuation of cardiac dysfunction and reversal of structural remodeling. SIRT4 may drive oxidative stress and fibrotic signaling via increased NOX4 expression (>7-fold), and/or direct modulation of potential SIRT4 targets newly identified by Human Protein Microarray, including calcitonin gene-related peptide receptor component protein, cyclophilin A, and interleukin-2 receptor β.

Conclusions

SIRT4 overexpression accelerates heart failure development in response to pressure overload, predominantly by ROS-mediated enhancement of profibrotic transcriptional signaling.
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来源期刊
Journal of molecular and cellular cardiology plus
Journal of molecular and cellular cardiology plus Cardiology and Cardiovascular Medicine
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