Ischemic but Not Pharmacological Preconditioning Requires Protein Synthesis

Matsuyama, Nanritsu; Leavens, John E.; McKinnon, David; Gaudette, Glenn R.; Aksehirli, Tunc O.; Krukenkamp, Irvin B.

doi:10.1161/circ.102.suppl_3.iii-312

Cited by 7 publications

(1 citation statement)

References 29 publications

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“…Jmjd4 loss-of-function did not affect Pkm2 transcript level (Figure S7C), suggesting that Jmjd4 regulates Pkm2 protein level through translational or posttranslational mechanisms. To investigate whether Pkm2 stability is altered by Jmjd4, we used cycloheximide, a protein synthesis inhibitor, 42 to block Pkm2 translation and assess the effects of Jmjd4 on its stability. Pkm2 protein level decreased significantly in NRVCs treated with cycloheximide (Figure S8A), and knocking down Jmjd4 in NRVCs blunted this effect (Figure S8B).…”

Section: Resultsmentioning

confidence: 99%

Jmjd4 Facilitates Pkm2 Degradation in Cardiomyocytes and Is Protective Against Dilated Cardiomyopathy

Tang

Feng

et al. 2023

Circulation

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BACKGROUND: A large portion of idiopathic and familial dilated cardiomyopathy (DCM) cases have no obvious causal genetic variant. Although altered response to metabolic stress has been implicated, the molecular mechanisms underlying the pathogenesis of DCM remain elusive. The JMJD family proteins, initially identified as histone deacetylases, have been shown to be involved in many cardiovascular diseases. Despite their increasingly diverse functions, whether JMJD family members play a role in DCM remains unclear. METHODS: We examined Jmjd4 expression in patients with DCM, and conditionally deleted and overexpressed Jmjd4 in cardiomyocytes in vivo to investigate its role in DCM. RNA sequencing, metabolites profiling, and mass spectrometry were used to dissect the molecular mechanism of Jmjd4-regulating cardiac metabolism and hypertrophy. RESULTS: We found that expression of Jmjd4 is significantly decreased in hearts of patients with DCM. Induced cardiomyocyte-specific deletion of Jmjd4 led to spontaneous DCM with severely impaired mitochondrial respiration. Pkm2, the less active pyruvate kinase compared with Pkm1, which is normally absent in healthy adult cardiomyocytes but elevated in cardiomyopathy, was found to be drastically accumulated in hearts with Jmjd4 deleted. Jmjd4 was found mechanistically to interact with Hsp70 to mediate degradation of Pkm2 through chaperone-mediated autophagy, which is dependent on hydroxylation of K66 of Pkm2 by Jmjd4. By enhancing the enzymatic activity of the abundant but less active Pkm2, TEPP-46, a Pkm2 agonist, showed a significant therapeutic effect on DCM induced by Jmjd4 deficiency, and heart failure induced by pressure overload, as well. CONCLUSION: Our results identified a novel role of Jmjd4 in maintaining metabolic homeostasis in adult cardiomyocytes by degrading Pkm2 and suggest that Jmjd4 and Pkm2 may be therapeutically targeted to treat DCM, and other cardiac diseases with metabolic dysfunction, as well.

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Section: Resultsmentioning

confidence: 99%

Jmjd4 Facilitates Pkm2 Degradation in Cardiomyocytes and Is Protective Against Dilated Cardiomyopathy

Tang

Feng

et al. 2023

Circulation

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Evidence of tanscriptional and tanslational components in anti‐ischemic effects of adenosine

Headrick

Peart

Holmgren

et al. 2003

Drug Development Research

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Adenosine protects against myocardial ischemic injury via poorly defined mechanisms. We examined effects of inhibition of gene transcription, mRNA translation, and mitochondrial K ATP channels on cardioprotective effects of adenosine in mouse hearts subjected to 20-min ischemia. Adenosine treatment reduced postischemic lactate dehydrogenase efflux (indicating necrosis) from 2472 to 971 IU/g, and postischemic diastolic contracture from 2172 to 572 mm Hg, and enhanced postischemic ventricular pressure development from 7273 to 13574 mm Hg. The antinecrotic response was reduced E50% by inhibition of protein translation (10 mM cycloheximide, CHX), unaltered by inhibition of transcription (20 mM actinomycin D, Act-D), and abrogated by mitochondrial K ATP channel inhibition (100 mM 5-hydroxydecanoate, 5-HD). In contrast, protection against contractile dysfunction was reduced but not eliminated by CHX, Act-D, and 5-HD, and inhibitory effects CHX and Act-D were not additive with those of 5-HD, supporting a common mechanistic path. Inhibitory effects of Act-D were mimicked by 1.5 mM a-amanitin. These data provide evidence that adenosine limits necrosis in a mito K ATP channel-dependent manner involving protein translation. The translational component is not dependent upon mRNA transcription. Adenosine also substantially reduces contractile dysfunction via a pathway involving mitochondrial K ATP channel activation, protein translation, and mRNA transcription. Protection independent of this path was also evident. Thus, distinct signaling pathways appear to be involved in adenosine-mediated protection against postischemic necrosis and contractile dysfunction. Drug Dev. Res. 58:454-460, 2003.

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Cardioprotection and Signaling Pathways

Marı́n-Garcı́a

2011

Signaling in the Heart

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Ischemic but Not Pharmacological Preconditioning Requires Protein Synthesis

Cited by 7 publications

References 29 publications

Jmjd4 Facilitates Pkm2 Degradation in Cardiomyocytes and Is Protective Against Dilated Cardiomyopathy

Jmjd4 Facilitates Pkm2 Degradation in Cardiomyocytes and Is Protective Against Dilated Cardiomyopathy

Evidence of tanscriptional and tanslational components in anti‐ischemic effects of adenosine

Cardioprotection and Signaling Pathways

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