Overexpression of a dominant-negative mutant of SIRT1 in mouse heart causes cardiomyocyte apoptosis and early-onset heart failure

Mu, Wenli; Zhang, QingJun; Tang, Xiaoqiang; Fu, Wenyan; Zheng, Wei; Lu, Yunbiao; Li, Hongliang; Wei, Yu‐Sheng; Li, Li; She, Zhi‐Gang; Chen, HouZao; Liu, Depei

doi:10.1007/s11427-014-4687-1

Cited by 25 publications

(14 citation statements)

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“…SIRT1 is expressed at high levels in prenatal hearts and is essential for cardiac development and prenatal survival2829. In cardiomyocytes, SIRT1 overexpression inhibited the expression of Nkx2.5 target genes, in part through repressing the interaction between Nkx2.5 and its transcriptional co-factors.…”

Section: Discussionmentioning

confidence: 99%

SIRT1 deacetylates the cardiac transcription factor Nkx2.5 and inhibits its transcriptional activity

Tang

Han

et al. 2016

Sci Rep

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The homeodomain transcription factor Nkx2.5/Csx is critically essential for heart specification, morphogenesis, and homeostasis. Acetylation/deacetylation is important for the localization, stability and activation of transcription factors. It remains unknown how Nkx2.5 is deacetylated and how Nkx2.5 acetylation determines its activity. In this study, we provide evidence that the NAD+-dependent class III protein deacetylase SIRT1 deacetylates Nkx2.5 in cardiomyocytes and represses the transcriptional activity of Nkx2.5. We show that SIRT1 interacts with the C-terminus of Nkx2.5 and deacetylates Nkx2.5 at lysine 182 in the homeodomain. The mutation of Nkx2.5 at lysine 182 reduces its transcriptional activity. Furthermore, SIRT1 inhibits the transcriptional activity of Nkx2.5 and represses the expression of its target genes partly by reducing Nkx2.5 binding to its co-factors, including SRF and TBX5. Taken together, these findings demonstrate that SIRT1 deacetylates Nkx2.5 and inhibits the transcriptional activity of Nkx2.5.

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Section: Discussionmentioning

confidence: 99%

SIRT1 deacetylates the cardiac transcription factor Nkx2.5 and inhibits its transcriptional activity

Tang

Han

et al. 2016

Sci Rep

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“…Abbreviation: VEGF, vascular endothelial cell growth factor. and VSMCs in CVDs [150][151][152]. As thus, β-hydroxybutyrate-mediated protection of vascular cell senescence may be partially mediated by p53 β-hydroxybutyrylation.…”

Section: Figure 7 Succinate In Cvdsmentioning

confidence: 92%

Short-chain fatty acid, acylation and cardiovascular diseases

2020

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Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide. Metabolic dysfunction is a fundamental core mechanism underlying CVDs. Previous studies generally focused on the roles of long-chain fatty acids (LCFAs) in CVDs. However, a growing body of study has implied that short-chain fatty acids (SCFAs: namely propionate, malonate, butyrate, 2-hydroxyisobutyrate (2-HIBA), β-hydroxybutyrate, crotonate, succinate, and glutarate) and their cognate acylations (propionylation, malonylation, butyrylation, 2-hydroxyisobutyrylation, β-hydroxybutyrylation, crotonylation, succinylation, and glutarylation) participate in CVDs. Here, we attempt to provide an overview landscape of the metabolic pattern of SCFAs in CVDs. Especially, we would focus on the SCFAs and newly identified acylations and their roles in CVDs, including atherosclerosis, hypertension, and heart failure. Clinical Science (2020) 134 657-676 https://doi.org/10.1042/CS20200128 cofactors in certain protein acylations, such as propionylation [14], malonylation [15], butyrylation [14], 2-hydroxyisobutyrylation [16], β-hydroxybutyrylation [17], crotonylation [18], succinylation [19], and glutarylation [20]. These discoveries give us a deeper understanding of PTM. Among PTMs, protein acetylation is the earliest discovered and most studied. Similar to protein acetylation, various studies have shown that these newly discovered PTMs are also involved in physiological and pathophysiological processes, including cardiovascular homeostasis.Here in this review, we will summarize SCFAs, protein acylations, and their emerging roles in CVDs, including atherosclerosis, hypertension, and heart failure. The metabolic pattern and FAs in CVDsThe heart is an 'omnivore' , using FAs, glucose, lactate, ketone bodies, and amino acids as metabolic substrates [5,6]. The substrates utilized by the embryonic heart are significantly different from those used by the adult heart. The embryonic heart depends primarily on glycolysis as well as lactate oxidation to produce energy [21]. The newborn and adult heart shift toward the remarkable utilization of FAs to meet cardiac energy demand [5,9]. In failing hearts, a decrease in FA oxidation and an increase in glycolysis are critically involved in cardiac dysfunction [22]. As thus, the metabolic pattern is essential for maintaining cardiac and vascular functions.Diabetes, hypertension, and obesity contribute to heart failure syndrome. Accumulating evidence suggests that hypertension, ischemic hearts, and heart failure induce a shift in substrate toward the remarkable utilization of glucose to generate energy. Despite this shift, the FA oxidation remains to make much energy for the diseased heart [23]. Since FAs are the predominant substrates for cardiomyocytes, alterations in FA metabolism have been implicated as causal in cardiac diseases. FAs within cells and in the circulation are critically involved in cardiometabolic diseases. CVDs are closely associated with lifestyle and metabolic status, which affect circul...

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“…Echocardiography was performed as per standard protocols [25]. In brief, Two-dimensional short-axis images were obtained using a high resolution Vevo 770 Imaging System (Visualsonics Inc.) equipped with a 35 MHz probe.…”

Section: Echocardiography Of Micementioning

confidence: 99%

The histone demethylase PHF8 represses cardiac hypertrophy upon pressure overload

Liu¹,

Wang²,

et al. 2015

Experimental Cell Research

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Overexpression of a dominant-negative mutant of SIRT1 in mouse heart causes cardiomyocyte apoptosis and early-onset heart failure

Cited by 25 publications

References 46 publications

SIRT1 deacetylates the cardiac transcription factor Nkx2.5 and inhibits its transcriptional activity

SIRT1 deacetylates the cardiac transcription factor Nkx2.5 and inhibits its transcriptional activity

Short-chain fatty acid, acylation and cardiovascular diseases

The histone demethylase PHF8 represses cardiac hypertrophy upon pressure overload

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