Opposing cardioprotective actions and parallel hypertrophic effects of δPKC and ɛPKC

Chen, Leon; Hahn, Harvey S.; Wu, Guangyu; Chen, Che Hong; Liron, Tamar; Schechtman, Deborah; Cavallaro, Gabriele; Banci, Lucia; Guo, Yiru; Bolli, Roberto; Dorn, Gerald W.; Mochly‐Rosen, Daria

doi:10.1073/pnas.191369098

Cited by 506 publications

(499 citation statements)

References 36 publications

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“…Indeed, it is known that up regulation of PKC-d is associated with the development of metastasis (see Debies & Welch 34 ). Activation of PKC-e is known to participate in the cardioprotective effects of preconditioning 35 while PKC-d is involved in the deleterious effects of ischaemia 36 . We observed that both PKC isoforms were less translocated to the particulate fraction in the fish oil diet group but this decrease was more pronounced for PKC-d than for PKC-e.…”

Section: Discussionmentioning

confidence: 99%

Dietary long-chainn-3 fatty acids modify blood and cardiac phospholipids and reduce protein kinase-C-δ and protein kinase-C-ε translocation

et al. 2007

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The effects of an n-3 PUFA-enriched diet on cardiac cell membrane phospholipid fraction compositions and associated protein kinase-C (PKC) translocation modification have never been studied in higher mammals. This is of importance since membrane fatty acid composition has been shown to influence PKC signalling pathways. In the present study, we have tested whether the incorporation of n-3 PUFA in cardiac membrane phospholipids correlated with changes in the fatty acid composition of diacylglycerols (DAG) and led to a differential translocation of PKC isoforms. Two groups of five dogs were fed the standard diet supplemented with palm oil or fish oil for 8 weeks. Dogs fed a fish oil-enriched diet showed a preferential incorporation of EPA and, to a lesser extent, of DHA, at the expense of arachidonic acid, in the circulating TAG, plasma phospholipids, erythrocyte phospholipids and cardiomyocyte phospholipid fractions. Analysis of 1,2-DAG fatty acid composition also indicated a preferential enrichment of EPA compared with DHA. Associated with these results, a reduction in the expression of PKC-δ and PKC-ε isoforms in the particulate fractions was observed whereas no effect was seen for PKC-α and PKC-ζ. We conclude that a fish oil-enriched diet induces a modification in fatty acid composition of cardiac membrane phospholipids, associated with a differential translocation of PKC isoforms. These results can be explained by the production of structurally different DAG that may participate in some of the protective effects of n-3 PUFA against various chronic diseases.

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Section: Discussionmentioning

confidence: 99%

Dietary long-chainn-3 fatty acids modify blood and cardiac phospholipids and reduce protein kinase-C-δ and protein kinase-C-ε translocation

et al. 2007

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“…Intraperitoneal injection of the dPKC-selective activator, cdRACK (Chen et al, 2001), after CCA release partially reversed the protective effect of hypothermia at 24 h ( Figure 9B). …”

Section: Partially Reverses the Protective Effect Of Hypothermiamentioning

confidence: 94%

Suppression of δPKC Activation after Focal Cerebral Ischemia Contributes to the Protective Effect of Hypothermia

Shimohata

Zhao

Sung

et al. 2007

J Cereb Blood Flow Metab

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Mild hypothermia is a robust neuroprotective treatment for stroke. Understanding the mechanisms underlying hypothermia's benefits will lead to more effective treatments to prevent stroke damage. Delta protein kinase C (dPKC) is a kinase that has been strongly implicated in executing ischemic damage. We investigated the effects of hypothermia on dPKC activation, as determined by its subcellular translocation, proteolytic cleavage, and phosphorylation in a focal cerebral ischemia model. The amount of constitutively activated C-terminal catalytic fragment of dPKC (CF-dPKC) increased after stroke. Both hypothermia (301C) and the caspase-3-specific inhibitor, Z-DQMD-FMK, blocked the accumulation of activated dPKC in the penumbra. Other hallmarks of dPKC activation, its translocation to the mitochondria, and nucleus were observed in the penumbra as early as 10 mins after reperfusion. These events were blocked by hypothermia. Hypothermia also blocked CF-dPKC increases in the mitochondria and nuclei. Conversely, a specific dPKC activator, wdRACK, decreased the neuroprotective effect of hypothermia. Finally, dPKC activity may lead to mitochondrial injury and cytochrome c release, as the timing of cytochrome c release corresponded to the time course of dPKC translocation. Both cytochrome c release and dPKC translocation were blocked by hypothermia. In conclusion, hypothermia protects against ischemic damage in part by suppressing dPKC activation after stroke.

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“…LDH assay kit was from Roche Molecular Biotechnology (Indianapolis, USA). The δPKC-specific antagonist peptide, δV1-1 (δPKC inhibitor, amino acids 8-17 [SFNSYELGSL]) was synthesized by American Peptides and conjugated to TAT-carrier peptide (amino acids 47-57) via a cysteine-cysteine S-S bond at their N termini, as previously described [14].…”

Section: Methodsmentioning

confidence: 99%

“…Twenty-four hours later, fresh serum-free medium was added and the myocytes were treated with tunicamycin as indicated in the figures. The δPKC-selective antagonist peptide, δV1-1, was conjugated to the TAT 47-57 carrier peptide for transmembrane delivery [14]. The unconjugated TAT 47-57 carrier peptide was used as a control.…”

Section: Isolation Of Rat Neonatal Cardiac Myocytesmentioning

confidence: 99%

“…However, whether δPKC participates in ER stress-induced cell death and apoptosis is not known. We therefore set out to determine whether cell death following ER stress is inhibited by the specific δPKC inhibitor peptide, δV1-1 [14]. Tunicamycin (Tm), a pharmacological agent inhibiting N-linked protein glycosylation, is commonly used to induce ER stress and subsequent cell death [4,[19][20][21].…”

Section: δPkc Inhibition Reduces Er Stress-induced Cell Death In Isolmentioning

confidence: 99%

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δPKC participates in the endoplasmic reticulum stress-induced response in cultured cardiac myocytes and ischemic heart

Vallentin

Churchill

et al. 2007

Journal of Molecular and Cellular Cardiology

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The cellular response to excessive endoplasmic reticulum (ER) stress includes the activation of signaling pathways, which lead to apoptotic cell death. Here we show that treatment of cultured cardiac myocytes with tunicamycin, an agent that induces ER stress, causes the rapid translocation of δPKC to the ER. We further demonstrate that inhibition of δPKC using the δPKC-specific antagonist peptide, δV1-1, reduces tunicamycin-induced apoptotic cell death, and inhibits expression of specific ER stress response markers such as CHOP, GRP78 and phosphorylation of JNK. The physiological importance of δPKC in this event is further supported by our findings that the ER stress response is also induced in hearts subjected to ischemia and reperfusion injury and that this response also involves δPKC translocation to the ER. We found that the levels of the ER chaperone, GRP78, the spliced XBP-1 and the phosphorylation of JNK are all increased following ischemia and reperfusion and that δPKC inhibition by δV1-1 blocks these events. Therefore, ischemia-reperfusion injury induces ER stress in the myocardium in a mechanism that requires δPKC activity. Taken together, our data show for the first time that δPKC activation plays a critical role in the ER stressmediated response and the resultant cell death.

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Opposing cardioprotective actions and parallel hypertrophic effects of δPKC and ɛPKC

Cited by 506 publications

References 36 publications

Dietary long-chainn-3 fatty acids modify blood and cardiac phospholipids and reduce protein kinase-C-δ and protein kinase-C-ε translocation

Dietary long-chainn-3 fatty acids modify blood and cardiac phospholipids and reduce protein kinase-C-δ and protein kinase-C-ε translocation

Suppression of δPKC Activation after Focal Cerebral Ischemia Contributes to the Protective Effect of Hypothermia

δPKC participates in the endoplasmic reticulum stress-induced response in cultured cardiac myocytes and ischemic heart

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