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 rema...

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Main Authors: 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, Peter P. Rainer, Simon Sedej, Daniel Scherr, Dirk von Lewinski, Adam R. Wende, Andreas Zirlik, Heiko Bugger
Format: Article
Language:English
Published: Elsevier 2025-06-01
Series:Journal of Molecular and Cellular Cardiology Plus
Subjects:
SIRT4
Sirtuin
Heart failure
Reactive oxygen species
Oxidative stress
Fibrosis
Online Access:http://www.sciencedirect.com/science/article/pii/S2772976125000182
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Summary: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.
ISSN:2772-9761

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