Dilated cardiomyopathy and mitochondrial dysfunction in Sirt1-deficient mice: A role for Sirt1-Mef2 in adult heart

Planavila, Anna; Domínguez, Elisabet; Navarro, Marc; Vinciguerra, Manlio; Iglesias, Roser; Giralt, Marta; Lope–Piedrafita, Silvia; Ruberte, Jesús; Villarroya, Francesc

doi:10.1016/j.yjmcc.2012.07.019

Cited by 82 publications

(59 citation statements)

References 38 publications

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“…Very recently, Planavila et al [38] showed that a small percentage of Sirt1 −/− mice that could survive to adulthood developed dilated cardiomyopathy, which is somewhat similar with the findings in TG founder mouse 50#. Thus, loss of SIRT1 deacetylase activity in the Sirt1 −/− survivors contributes to dilated cardiomyopathy in late stage of postnatal hearts.…”

Section: Discussionmentioning

confidence: 61%

“…Both the mitochondrial and death receptor-initiated pathways have been shown to activate caspase-3, which is sufficient to induce cardiomyocyte apoptosis and dilated cardiomyopathy [40]. In the previous study, Planavila et al [38] observed dilated cardiomyopathy and mitochondria dysfunction in SIRT1-deficient mice. They attributed those effects to Mef2, which is crucial both for cardiac differentiation and heart-specific gene expression and also for the control of mitochondrial biogenesis.…”

Section: Discussionmentioning

confidence: 94%

“…Thus, loss of SIRT1 deacetylase activity in the Sirt1 −/− survivors contributes to dilated cardiomyopathy in late stage of postnatal hearts. Here we used dominant negative form of SIRT1 (SIRT1H363Y) overexpression to inhibit the deacetylase of SIRT1, whereas the study of Planavila et al used knockout mice expressing a deacetylase-activity absent form of SIRT1 protein [38]. Compared to loss-of-function mutation of SIRT1 protein, dominant negative form of SIRT1 (SIRT1H363Y) protein has potential dominant negative effects on cardiac functions, which may explain the more severe phenotype of our transgenic mice, including the earlier onset of cardiomyopathy and heart failure.…”

Section: Discussionmentioning

confidence: 99%

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

Zhang

Tang

et al. 2014

Sci. China Life Sci.

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SIRT1, a mammalian ortholog of yeast silent information regulator 2 (Sir2), is an NAD + -dependent protein deacetylase that plays a critical role in the regulation of vascular function. The current study aims to investigate the functional significance of deacetylase activity of SIRT1 in heart. Here we show that the early postnatal hearts expressed the highest level of SIRT1 deacetylase activity compared to adult and aged hearts. We generated transgenic mice with cardiac-specific expression of a dominant-negative form of the human SIRT1 (SIRT1H363Y), which represses endogenous SIRT1 activity. The transgenic mice displayed dilated atrial and ventricular chambers, and died early in the postnatal period. Pathological, echocardiographic and molecular phenotype confirmed the presence of dilated cardiomyopathy. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling analysis revealed a greater abundance of apoptotic nuclei in the hearts of transgenic mice. Furthermore, we show that cardiomyocyte apoptosis caused by suppression of SIRT1 activity is, at least in part, due to increased p53 acetylation and upregulated Bax expression. These results indicate that dominant negative form of SIRT1 (SIRT1H363Y) overexpression in mouse hearts causes cardiomyocyte apoptosis and early-onset heart failure, suggesting a critical role of SIRT1 in preserving normal cardiac development during the early postnatal period. deacetylase, SIRT1, apoptosis, heart failure Citation:

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Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

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

Zhang

Tang

et al. 2014

Sci. China Life Sci.

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“…Previous studies have indicated that the loss of SIRT1 led to dilated cardiomyopathy and mitochondrial abnormality in the adult hearts of SIRT1-deficient mice. 30 Recently, several reports demonstrated that ANG II reduces SIRT1 expression, whereas the ANG II-induced cell hypertrophy is diminished by the activation of SIRT1. 31,32 Moreover, the administration of RSV, a specific SIRT1 activator, suppressed cardiac hypertrophy and restored cardiac function, suggesting that SIRT1 is essential for cardiomyocyte development.…”

Section: Discussionmentioning

confidence: 99%

ANG II promotes IGF-IIR expression and cardiomyocyte apoptosis by inhibiting HSF1 via JNK activation and SIRT1 degradation

Huang

et al. 2014

Cell Death Differ

115

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Hypertension-induced cardiac hypertrophy and apoptosis are major characteristics of early-stage heart failure. Our previous studies found that the activation of insulin-like growth factor receptor II (IGF-IIR) signaling was critical for hypertensive angiotensin II (ANG II)-induced cardiomyocyte apoptosis. However, the detailed mechanism by which ANG II regulates IGF-IIR in heart cells remains elusive. In this study, we found that ANG II activated its downstream kinase JNK to increase IGF-IIR expression through the ANG II receptor angiotensin type 1 receptor. JNK activation subsequently led to sirtuin 1 (SIRT1) degradation via the proteasome, thus preventing SIRT1 from deacetylating heat-shock transcription factor 1 (HSF1). The resulting increase in the acetylation of HSF1 impaired its ability to bind to the IGF-IIR promoter region (nt À 748 to À 585). HSF1 protected cardiomyocytes by acting as a repressor of IGF-IIR gene expression, and ANG II diminished this HSF1-mediated repression through enhanced acetylation, thus activating the IGF-IIR apoptosis pathway. Taken together, these results suggest that HSF1 represses IGF-IIR gene expression to protect cardiomyocytes. ANG II activates JNK to degrade SIRT1, resulting in HSF1 acetylation, which induces IGF-IIR expression and eventually results in cardiac hypertrophy and apoptosis. HSF1 could be a valuable target for developing treatments for cardiac diseases in hypertensive patients. Apoptosis has been implicated in a wide variety of cardiovascular disorders, including myocardial infarction and heart failure, suggesting that activation of apoptotic pathways contributes to cardiomyocyte loss and subsequently cardiac dysfunction. Previous studies reported that several extracellular molecules, such as insulin-like growth factors (IGFs) and angiotensin II (ANG II), are involved in the development of cardiac hypertrophy and apoptosis.

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“…99 Hence, loss of SIRT1 activity leads to dilated cardiomyopathy in adult hearts accompanied with mitochondrial dysfunction and reduced mitochondrial gene expression. 100 Nevertheless, SIRT1 also controls the acetylation status of MEF2 transcription factors, which as outlined above regulate PGC-1α expression. Intriguingly, Zhao et al showed that MEF2 is modified by either acetylation or SUMOylation.…”

mentioning

confidence: 99%

The Ubiquitin-Like SUMO System and Heart Function

Mendler

Braun

Müller

2016

Circulation Research

101

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Dilated cardiomyopathy and mitochondrial dysfunction in Sirt1-deficient mice: A role for Sirt1-Mef2 in adult heart

Cited by 82 publications

References 38 publications

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

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

ANG II promotes IGF-IIR expression and cardiomyocyte apoptosis by inhibiting HSF1 via JNK activation and SIRT1 degradation

The Ubiquitin-Like SUMO System and Heart Function

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