Methylation of the Hippo effector YAP by the methyltransferase SETD7 drives myocardial ischaemic injury: a translational study

Ambrosini, Samuele; Montecucco, Fabrizio; Kolijn, Detmar; Pedicino, Daniela; Akhmedov, Alexander; Mohammed, Shafeeq Ahmed; Herwig, Melissa; Gorica, Era; Szabó, Petra Lujza; Weber, Lukas; Russo, Giulio; Vinci, Ramona; Matter, Christian M; Liuzzo, Giovanna; Brown, Peter J.; Rossi, Fábio; Camici, Giovanni G.; Sciarretta, Sebastiano; Beltrami, Antonio Paolo; Crea, Filippo; Podesser, Bruno K.; Lüscher, Thomas F.; Kiss, Attila; Ruschitzka, Frank; Hamdani, Nazha; Costantino, Sarah; Paneni, Francesco

doi:10.1093/cvr/cvac102

Cited by 18 publications

(18 citation statements)

References 34 publications

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“…Within hours, a regulated inflammatory response consisting mainly of neutrophils and monocyte/macrophages is initiated in the myocardium to remove dead cells and matrix debris 38 . In addition, apoptotic cardiomyocytes induced by myocardial inflammatory response are present in the surviving portion of the wall adjacent to the ischemic area 39 . The present study has shown that WWP1 governs an inflammatory program in cardiomyocytes to increase myocardial inflammation and apoptosis after MI.…”

Section: Discussionmentioning

confidence: 99%

Targeting WWP1 ameliorates cardiac ischemic injury by suppressing KLF15-ubiquitination mediated myocardial inflammation

Lu¹,

Yang²,

Qi³

et al. 2023

Theranostics

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Rationale: Previous studies have suggested that myocardial inflammation plays a critical role after ischemic myocardial infarction (MI); however, the underlying mechanisms still need to be fully elucidated. WW domain-containing ubiquitin E3 ligase 1 (WWP1) is considered as an important therapeutic target for cardiovascular diseases due to its crucial function in non-ischemic cardiomyopathy, though it remains unknown whether targeting WWP1 can alleviate myocardial inflammation and ischemic injury post-MI. Methods: Recombinant adeno-associated virus 9 (rAAV9)-cTnT-mediated WWP1 or Kruppel-like factor 15 (KLF15) gene transfer and a natural WWP1 inhibitor Indole-3-carbinol (I3C) were used to determine the WWP1 function in cardiomyocytes. Cardiac function, tissue injury, myocardial inflammation, and signaling changes in the left ventricular tissues were analyzed after MI. The mechanisms underlying WWP1 regulation of cardiomyocyte phenotypes in vitro were determined using the adenovirus system. Results: We found that WWP1 expression was up-regulated in cardiomyocytes located in the infarct border at the early phase of MI and in hypoxia-treated neonatal rat cardiac myocytes (NRCMs). Cardiomyocyte-specific WWP1 overexpression augmented cardiomyocyte apoptosis, increased infarct size and deteriorated cardiac function. In contrast, inhibition of WWP1 in cardiomyocytes mitigated MI-induced cardiac ischemic injury. Mechanistically, WWP1 triggered excessive cardiomyocyte inflammation after MI by targeting KLF15 to catalyze K48-linked polyubiquitination and degradation. Ultimately, WWP1-mediated degradation of KLF15 contributed to the up-regulation of p65 acetylation, and activated the inflammatory signaling of MAPK in ischemic myocardium and hypoxia-treated cardiomyocytes. Thus, targeting of WWP1 by I3C protected against cardiac dysfunction and remodeling after MI. Conclusions: Our study provides new insights into the previously unrecognized role of WWP1 in cardiomyocyte inflammation and progression of ischemic injury induced by MI. Our findings afford new therapeutic options for patients with ischemic cardiomyopathy.

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Section: Discussionmentioning

confidence: 99%

Targeting WWP1 ameliorates cardiac ischemic injury by suppressing KLF15-ubiquitination mediated myocardial inflammation

Lu¹,

Yang²,

Qi³

et al. 2023

Theranostics

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“…Under physiological conditions, a small proportion of ROS generated is rapidly scavenged by internal antioxidative systems 32 . However, these systems are severely disrupted during I/R, which contributes to excessive ROS production and leads to the initial myocardial reperfusion injury 33 . Thus, enhancing the activity of antioxidative enzymes may be a good strategy to decrease the oxidative stress‐elicited reperfusion damage 34,35 .…”

Section: Discussionmentioning

confidence: 99%

N‐n‐butyl haloperidol iodide mediates cardioprotection via regulating AMPK/FoxO1 signalling

Lu,

Wu,

et al. 2023

J Cellular Molecular Medi

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Derangement of redox condition largely contributes to cardiac ischemia/reperfusion (I/R) injury. FoxO1 is a transcription factor which transcripts a series of antioxidants to antagonize I/R‐induced oxidative myocardial damage. N‐n‐butyl haloperidol iodide (F2) is a derivative derived from haloperidol structural modification with potent capacity of inhibiting oxidative stress. This investigation intends to validate whether cardio‐protection of F2 is dependent on FoxO1 using an in vivo mouse I/R model and if so, to further elucidate the molecular regulating mechanism. This study initially revealed that F2 preconditioning led to a profound reduction in I/R injury, which was accompanied by attenuated oxidative stress and upregulation of antioxidants (SOD2 and catalase), nuclear FoxO1 and phosphorylation of AMPK. Furthermore, inactivation of FoxO1 with AS1842856 abolished the cardio‐protective effect of F2. Importantly, we identified F2‐mediated nuclear accumulation of FoxO1 is dependent on AMPK, as blockage of AMPK with compound C induced nuclear exit of FoxO1. Collectively, our data uncover that F2 pretreatment exerts significant protection against post ischemic myocardial injury by its regulation of AMPK/FoxO1 pathway, which may provide a new avenue for treating ischemic disease.

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“…In addition to SET1A, the methylation of YAP can also be induced by suppressor of variegation 3‐9‐enhancer of zeste‐trithorax domain containing lysin E methyltransferase 7 (SETD7). SETD7 can methylate the YAP at lysine 494 to inhibit the transfer of YAP to the nucleus, thus reducing the transcription of antioxidant genes manganese superoxide dismutase (MnSOD) and catalase (CAT) ultimately to protect the heart 131 . Spectrin beta, nonerythrocytic 1 (SPTBN1) can promote the expression of SETD7 to enhance YAP methylation, and ultimately plays a role in cell autophagy 132 …”

Section: The Regulation Of Yap/tazmentioning

confidence: 99%

“…SETD7 can methylate the YAP at lysine 494 to inhibit the transfer of YAP to the nucleus, thus reducing the transcription of antioxidant genes manganese superoxide dismutase (MnSOD) and catalase (CAT) ultimately to protect the heart. 131 Spectrin beta, nonerythrocytic 1 (SPTBN1) can promote the expression of SETD7 to enhance YAP methylation, and ultimately plays a role in cell autophagy. 132 The O-GlcNAcylation of YAP has been mentioned above.…”

Section: 8mentioning

confidence: 99%

YAP/TAZ: Molecular pathway and disease therapy

Wei,

Hui,

Chen

et al. 2023

MedComm

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The Yes‐associated protein and its transcriptional coactivator with PDZ‐binding motif (YAP/TAZ) are two homologous transcriptional coactivators that lie at the center of a key regulatory network of Hippo, Wnt, GPCR, estrogen, mechanical, and metabolism signaling. YAP/TAZ influences the expressions of downstream genes and proteins as well as enzyme activity in metabolic cycles, cell proliferation, inflammatory factor expression, and the transdifferentiation of fibroblasts into myofibroblasts. YAP/TAZ can also be regulated through epigenetic regulation and posttranslational modifications. Consequently, the regulatory function of these mechanisms implicates YAP/TAZ in the pathogenesis of metabolism‐related diseases, atherosclerosis, fibrosis, and the delicate equilibrium between cancer progression and organ regeneration. As such, there arises a pressing need for thorough investigation of YAP/TAZ in clinical settings. In this paper, we aim to elucidate the signaling pathways that regulate YAP/TAZ and explore the mechanisms of YAP/TAZ‐induce diseases and their potential therapeutic interventions. Furthermore, we summarize the current clinical studies investigating treatments targeting YAP/TAZ. We also address the limitations of existing research on YAP/TAZ and propose future directions for research. In conclusion, this review aims to provide fresh insights into the signaling mediated by YAP/TAZ and identify potential therapeutic targets to present innovative solutions to overcome the challenges associated with YAP/TAZ.

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Methylation of the Hippo effector YAP by the methyltransferase SETD7 drives myocardial ischaemic injury: a translational study

Cited by 18 publications

References 34 publications

Targeting WWP1 ameliorates cardiac ischemic injury by suppressing KLF15-ubiquitination mediated myocardial inflammation

Targeting WWP1 ameliorates cardiac ischemic injury by suppressing KLF15-ubiquitination mediated myocardial inflammation

N‐n‐butyl haloperidol iodide mediates cardioprotection via regulating AMPK/FoxO1 signalling

YAP/TAZ: Molecular pathway and disease therapy

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