Myocardial healing requires Reg3β-dependent accumulation of macrophages in the ischemic heart

Lörchner, Holger; Pöling, Jochen; Gajawada, Praveen; Hou, Yunlong; Polyakova, V.; Kostin, Sawa; Adrian-Segarra, Juan M.; Boettger, Thomas; Wietelmann, Astrid; Warnecke, H.; Richter, Manfred; Kubin, Thomas; Braun, Thomas

doi:10.1038/nm.3816

Cited by 148 publications

(138 citation statements)

References 60 publications

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“…Tissue samples were characterized by hematoxylin and eosin staining (H&E) (Chroma/Waldeck) according to standard protocols. Samples for fluorescence microscopy were processed as previously described (49). All MRI measurements were performed on a 7.0T superconducting magnet (Pharmascan, 70/16, 16 cm; Bruker Biospin) equipped with an actively shielded imaging gradient field of 760 mT/m using established methods (50).…”

Section: Methodsmentioning

confidence: 99%

Sirt7 promotes adipogenesis in the mouse by inhibiting autocatalytic activation of Sirt1

Fang

Ianni

Smolka

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Sirtuins (Sirt1-Sirt7) are NAD + -dependent protein deacetylases/ ADP ribosyltransferases, which play decisive roles in chromatin silencing, cell cycle regulation, cellular differentiation, and metabolism. Different sirtuins control similar cellular processes, suggesting a coordinated mode of action but information about potential cross-regulatory interactions within the sirtuin family is still limited. Here, we demonstrate that Sirt1 requires autodeacetylation to efficiently deacetylate targets such as p53, H3K9, and H4K16. Sirt7 restricts Sirt1 activity by preventing Sirt1 autodeacetylation causing enhanced Sirt1 activity in Sirt7 −/− mice. Increased Sirt1 activity in Sirt7 −/− mice blocks PPARγ and adipocyte differentiation, thereby diminishing accumulation of white fat. Thus, reduction of Sirt1 activity restores adipogenesis in Sirt7 −/− adipocytes in vitro and in vivo. We disclosed a principle controlling Sirt1 activity and uncovered an unexpected complexity in the crosstalk between two different sirtuins. We propose that antagonistic interactions between Sirt1 and Sirt7 are pivotal in controlling the signaling network required for maintenance of adipose tissue.sirtuin | acetylation | adipogenesis T he seven sirtuins in mammals (Sirt1-Sirt7) are involved in the regulation of essential cellular processes. Sirtuins rapidly adjust the activity of chromatin, transcription factors, metabolic enzymes, and structural proteins to cellular needs by deacetylating a broad range of targets. The ability to sense metabolic alterations and various stressors enable sirtuins to adapt cellular homeostasis to varying conditions. It seems likely that this feature of sirtuins is crucial to prevent age-dependent pathologies and promote a healthy lifespan (1, 2).Sirt1 is the most widely studied mammalian sirtuin showing the highest homology to the founding member of the sirtuin family, the yeast silence information regulator, Sir2. Sirt1 deacetylates histones H3K9, H3K56, H4K16, and H1K26 as well as many nonhistone targets thereby contributing to the maintenance of metabolic homeostasis and genomic integrity (3, 4). Sirt1 was also identified as a critical component of lifespan extension in response to calorie restriction in several model organisms, although its exact contribution is still under debate (5). The functions of Sirt7 have attracted less attention compared with Sirt1.

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Section: Methodsmentioning

confidence: 99%

Sirt7 promotes adipogenesis in the mouse by inhibiting autocatalytic activation of Sirt1

Fang

Ianni

Smolka

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…An in vivo model of coronary ischemia, induced via left anterior descending artery ligation, has been used to investigate the effect of fondaparinux administered in whole blood. Results revealed a 29 % reduction in infarct size following ischemia/reperfusion injury in vivo [64]. The addition of AG490 prevented STAT3 phosphorylation and abolished the cardioprotective effect of fondaparinux [64].…”

Section: Stat3 and Inflammationmentioning

confidence: 96%

“…Results revealed a 29 % reduction in infarct size following ischemia/reperfusion injury in vivo [64]. The addition of AG490 prevented STAT3 phosphorylation and abolished the cardioprotective effect of fondaparinux [64].…”

Section: Stat3 and Inflammationmentioning

confidence: 96%

Understanding STAT3 signaling in cardiac ischemia

et al. 2016

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Cardiovascular disease is the leading cause of death worldwide. It remains one of the greatest challenges to global health and will continue to dominate mortality trends in the future. Acute myocardial infarction results in 7.4 million deaths globally per annum. Current management strategies are centered on restoration of coronary blood flow via percutaneous coronary intervention, coronary artery bypass grafting and administration of anti-platelet agents. Such myocardial reperfusion accounts for 40-50 % of the final infarct size in most cases. Signaling transducer and activator of transcription 3 (STAT3) has been shown to have cardioprotective effects via canonical and non-canonical activation and modulation of mitochondrial and transcriptional responses. A significant body of in vitro and in vivo evidence suggests that activation of the STAT3 signal transduction pathway results in a cardio protective response to ischemia and attempts have been made to modulate this with therapeutic effect. Not only is STAT3 important for cardiomyocyte function, but it also modulates the cardiac microenvironment and communicates with cardiac fibroblasts. To this end, we here review the current evidence supporting the manipulation of STAT3 for therapeutic benefit in cardiac ischemia and identify areas for future research.

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“…The study by Lö rchner et al (2015) challenges the notion that cardiomyocytes are static cells, destined to suffer the consequences of the pro-inflammatory environment in the healing infarct. When stimulated by cytokines, viable cardiomyocytes in the infarct border zone respond by activating anti-inflammatory and reparative cascades.…”

Section: Discussionmentioning

confidence: 99%

“…Viable cardiomyocytes in the infarct border zone are directly exposed to the inflammatory environment of the infarct and may form the ''first line of defense,'' protecting the non-infarcted myocardium from inflammatory injury. In a recently published study in Nature Medicine, Lö rchner and co-workers demonstrated that surviving cardiomyocytes in the infarct border zone are crucial and dynamic regulators of post-infarction inflammation and repair (Lö rchner et al, 2015). Using a combination of in vivo and in vitro strategies, the authors found that border zone cardiomyocytes promote repair by releasing Reg3b, a small secretory protein that modulates leukocyte function.…”

mentioning

confidence: 99%