Mitochondrial translocation of Nur77 mediates cardiomyocyte apoptosis

Cheng, Zhaokang; Völkers, Mirko; Din, Shabana; Avitabile, Daniele; Khan, Mohsin; Gude, Natalie; Mohsin, Sadia; Bo, Tao; Truffa, Silvia; Álvarez, Roberto Baelo; Mason, Matt; Fischer, Kimberlee M.; Konstandin, Mathias; Zhang, Xiao Kun; Brown, Joan Heller; Sussman, Mark A.

doi:10.1093/eurheartj/ehq496

Cited by 85 publications

(79 citation statements)

References 43 publications

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“…Given these results, it is possible that cardiac NR4A1 is activated in the heart under stress conditions such as adrenergic stimulation to regulate metabolism as a stress response. However, other studies have demonstrated that NR4A1 exits the nucleus and translocates to the mitochondria to facilitate cytochrome C release and stimulate apoptosis (43). In support of this model, loss of NR4A1 protects the heart from angiotensin II-induced cardiac hypertrophy (44).…”

Section: Control Of Cardiac Fuel Metabolism By Other Nuclear Receptorsmentioning

confidence: 90%

Cardiac nuclear receptors: architects of mitochondrial structure and function

Vega¹,

Kelly²

2017

Journal of Clinical Investigation

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The adult mammalian heart has immense energy demands in order to support its role as a constantly active pump. Indeed, the human heart generates and utilizes kilogram quantities of ATP each day. The vast majority of ATP produced in the cardiac myocyte is generated via oxidative phosphorylation (OXPHOS) within a very-high-capacity mitochondrial system. The heart must continually adapt to changing physiologic conditions that influence workload, as well as alterations in oxygen and energy substrate availability. Notably, given that the heart has a limited capacity for fuel storage, it must utilize several energy substrates in an efficient and dynamic manner. As will be described, members of the nuclear receptor transcription factor superfamily serve to dynamically control preference and capacity for cardiac mitochondrial fuel metabolism during development and in response to myriad physiologic conditions. In addition, alterations in nuclear receptor signaling occur with pathologic cardiac growth and remodeling en route to heart failure.The adult cardiac myocyte has a higher density of mitochondria than any other cell type (1). The biogenesis of this highcapacity mitochondrial system occurs largely during the perinatal stage of development. This process involves a major burst of mitochondrial biogenesis at birth, followed by a period of mitochondrial maturation and remodeling during the postnatal period (2). Recent evidence indicates that postnatal mitochondrial maturation involves highly coordinated events including mitophagy, biogenesis, and dynamics (fusion and fission), resulting in a mitochondria network that is densely packed between sarcomeres to directly supply ATP to support cardiac contraction (2). The adult cardiac mitochondria are equipped with enzymatic machinery capable of oxidizing multiple substrates including fatty acids (the chief fuel) as well as glucose (pyruvate) and ketone bodies. This mitochondrial developmental maturation process occurs in parallel with well-characterized changes in the expression of contractile apparatus isoforms, ion channels, and calcium handling proteins. The collective perinatal programming in energy metabolic and structural genes results in an efficient and enduring pump for the adult life of the organism.The postnatal heart has an amazing capacity to oxidize multiple fuels and, therefore, is "omnivorous." Pioneering work by multiple groups has defined dynamic shifts in fuel utilization capacity and preferences during development and in disease states. The fetal and immediate postnatal heart relies primarily on glucose (glycolysis) and lactate as energy sources (3-5). However, very soon after birth the heart shifts to fatty acids as the major fuel substrate, coincident with the mitochondrial biogenic response (Figure 1 and refs. 5-8). The level of glucose oxidation also increases (8). The postnatal heart is also capable of oxidizing ketones, albeit at a low level, concomitant with the postnatal rise in circulating ketones (5). The shifts in fuel preference after birth ar...

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Section: Control Of Cardiac Fuel Metabolism By Other Nuclear Receptorsmentioning

confidence: 90%

Cardiac nuclear receptors: architects of mitochondrial structure and function

Vega¹,

Kelly²

2017

Journal of Clinical Investigation

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“…and cardiac ischemia/reperfusion injury). [8][9][10] In VSMCs, Nur77 can be induced by multiple stimuli, including cytokines, growth factors, oxidized low-density lipoprotein, and vascular injury. 11,25,26 We found that Nur77 was highly expressed in medial VSMCs of thoracic aortas from Ang II-infused mice in vivo and in cultured VSMCs after Ang II stimulation in vitro.…”

Section: Discussionmentioning

confidence: 99%

Orphan Nuclear Receptor Nur77 Inhibits Angiotensin II–Induced Vascular Remodeling via Downregulation of β-Catenin

et al. 2016

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Angiotensin II (Ang II) is the predominant effector peptide of the renin–angiotensin system. Ang II contributes to vascular remodeling in many cardiovascular diseases (eg, hypertension, atherosclerosis, restenosis, and aneurysm). Orphan nuclear receptor Nur77 has a crucial role in the functional regulation of vascular cells. The objective of this study was to define the specific role of Nur77 in Ang II–induced vascular remodeling. Nur77 expression was initially found to be elevated in medial vascular smooth muscle cells (VSMCs) of thoracic aortas from mice continuously infused with Ang II for 2 weeks using a subcutaneous osmotic minipump. Cellular studies revealed that Nur77 expression was upregulated by Ang II via the MAPK/PKA-CREB signaling pathway. Ang II–induced proliferation, migration, and phenotypic switching were significantly enhanced in VSMCs isolated from Nur77 −/− mice compared with wild-type VSMCs. Consistent with the role in VSMCs, we found that compared with wild-type mice, Nur77 −/− mice had elevated aortic medial areas and luminal diameters, more severe elastin disruption and collagen deposition, increased VSMC proliferation and matrix metalloproteinase production, and decreased VSMC-specific genes SM-22α and α-actin expression, after 2 weeks of exogenous Ang II administration. The results of additional experiments suggested that Nur77 suppressed Ang II–induced β-catenin signaling pathway activation by promoting β-catenin degradation and inhibiting its transcriptional activity. Our findings indicated that Nur77 is a critical negative regulator of Ang II–induced VSMC proliferation, migration, and phenotypic switching via the downregulation of β-catenin activity. Nur77 may reduce Ang II–induced vascular remodeling involved in many cardiovascular diseases.

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“…Accumulating evidence suggests that NR4A receptors play essential roles in the development of atherosclerosis, restenosis, and angiogenesis (17,18,33). However, the functional role of the NR4A receptor in cardiomyocyte biology remains largely obscured, although several studies suggest that the NR4A receptors are highly expressed in the heart and that their expression is regulated by several external pathological stimuli, such as oxidative stress, pressure overload, and ␤-AR activation (19,20,34). In the present study, we sought to examine the role of Nur77 in cardiac hypertrophy and found that the expression of Nur77 is substantially increased in response to a wide range of hypertrophic stimuli.…”

Section: Discussionmentioning

confidence: 99%

“…Most importantly, our recent study has implicated Nur77 as a potent negative regulator for the proinflammatory response in ECs via a selective inhibition of NF-B activation (18). In cardiomyocytes, Nur77 expression can be induced by ischemia/reperfusion injury, and translocation of Nur77 to the mitochondria mediates cardiomyocyte apoptosis in response to oxidative stress (19). Interestingly, a recent report demonstrated that the expression of Nur77 in the heart was rapidly induced in vivo following ␤-adrenergic stimulation (20,21).…”

mentioning

confidence: 98%

Orphan Nuclear Receptor Nur77 Inhibits Cardiac Hypertrophic Response to Beta-Adrenergic Stimulation

Yan

Zhu

Huang

et al. 2015

Molecular and Cellular Biology

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The orphan nuclear receptor Nur77 plays critical roles in cardiovascular diseases, and its expression is markedly induced in the heart after beta-adrenergic receptor (␤-AR) activation. However, the functional significance of Nur77 in ␤-AR signaling in the heart remains unclear. By using Northern blot, Western blot, and immunofluorescent staining assays, we showed that Nur77 expression was markedly upregulated in cardiomyocytes in response to multiple hypertrophic stimuli, including isoproterenol (ISO), phenylephrine (PE), and endothelin-1 (ET-1). In a time-and dose-dependent manner, ISO increases Nur77 expression in the nuclei of cardiomyocytes. Overexpression of Nur77 markedly inhibited ISO-induced cardiac hypertrophy by inducing nuclear translocation of Nur77 in cardiomyocytes. Furthermore, cardiac overexpression of Nur77 by intramyocardial injection of Ad-Nur77 substantially inhibited cardiac hypertrophy and ameliorated cardiac dysfunction after chronic infusion of ISO in mice. Mechanistically, we demonstrated that Nur77 functionally interacts with NFATc3 and GATA4 and inhibits their transcriptional activities, which are critical for the development of cardiac hypertrophy. These results demonstrate for the first time that Nur77 is a novel negative regulator for the ␤-AR-induced cardiac hypertrophy through inhibiting the NFATc3 and GATA4 transcriptional pathways. Targeting Nur77 may represent a potentially novel therapeutic strategy for preventing cardiac hypertrophy and heart failure. Cardiac hypertrophy is an adaptive process in response to various physiological or pathological stimuli associated with neurohumoral activation, elevated wall stress, and changes in volume load (1). Although initially adaptive, persistent hypertrophy induced by pathological conditions like myocardial infarction and hypertension has detrimental consequences on the heart and eventually progresses to heart failure, a major cause of death and disability in the industrialized world (1). At cellular and molecular levels, cardiac hypertrophy is characterized by increased myocyte size, sarcomerogenesis, and reexpression of a set of fetal genes, such as the atrial natriuretic factor, B-type natriuretic peptide, and ␤-myosin heavy chain genes, which are coordinately controlled by a subset of hypertrophy-responsive transcription factors, including myocyte enhancer factor 2 (MEF2), nuclear factor of activated T cells (NFAT), and GATA4 (2, 3) (4). Depending on the upstream hypertrophic stimuli, these transcriptional regulators can be directly phosphorylated or dephosphorylated by protein kinases, such as mitogen-activated protein (MAP) kinase and protein kinases A and C, as well as the calcium-activated phosphatase calcineurin, to facilitate hypertrophic gene expression (5-9). Disruption and/or attenuation of the activities of these transcription factors could serve as a potential therapeutic approach in terms of inhibiting the hypertrophic responses in the heart (10-12).NR4A receptors are immediate early genes that are regulated by various ...

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Mitochondrial translocation of Nur77 mediates cardiomyocyte apoptosis

Cited by 85 publications

References 43 publications

Cardiac nuclear receptors: architects of mitochondrial structure and function

Cardiac nuclear receptors: architects of mitochondrial structure and function

Orphan Nuclear Receptor Nur77 Inhibits Angiotensin II–Induced Vascular Remodeling via Downregulation of β-Catenin

Orphan Nuclear Receptor Nur77 Inhibits Cardiac Hypertrophic Response to Beta-Adrenergic Stimulation

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