Formation of protein kinase Cε-Lck signaling modules confers cardioprotection

Ping, Peipei; Song, Changxu; Zhang, Jun; Guo, Yiru; Cao, Xinan; Li, Richard C.X.; Wu, Wenjian; Vondriska, Thomas M.; Pass, Jason M.; Tang, Xian Liang; Pierce, William M.; Bolli, Roberto

doi:10.1172/jci13200

Cited by 68 publications

(34 citation statements)

References 39 publications

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“…When interpreting these results it should be stressed that chelerythrine is a non specific PKC inhibitor, while T 1 AM might activate a specific PKC isoform, e.g. PKC-ε, which has been associated with the cardioprotection produced by ischemic preconditioning or pharmacological interventions [15,16].…”

Section: Discussionmentioning

confidence: 99%

Cardioprotective Effect of 3-Iodothyronamine in Perfused Rat Heart Subjected to Ischemia and Reperfusion

Frascarelli

Ghelardoni

Chiellini

et al. 2011

Cardiovasc Drugs Ther

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3-iodothyronamine (T(1)AM) is an endogenous compound which shares structural and functional features with biogenic amines and is able to interact with a specific class of receptors, designed as trace amine associated receptors. T(1)AM has significant physiological effects in mammals and produces a reversible, dose-dependent negative inotropic and chronotropic effect in heart. The aim of the present study was to investigate if T(1)AM is able to reduce irreversible tissue injury in isolated rat hearts subjected to ischemia and reperfusion, as evaluated by triphenyltetrazolium chloride staining. We observed that T(1)AM reduced infarct size at concentrations (125 nM to 12.5 μM) which did not produce any significant hemodynamic action. The dose-response curve was bell-shaped and peaked at 1.25 μM. T(1)AM-induced cardioprotection was completely reversed by the administration of chelerythrine and glibenclamide, suggesting a protein kinase C and K (ATP) (+) -dependent pathway, while it was not additive to the protection induced by cyclosporine A, suggesting modulation of mitochondrial permeability transition. At cardioprotective concentration, T(1)AM reduced the time needed for cardiac attest during ischemia, but it did not affect sarcoplasmatic reticulum Ca(2+) handling, as demonstrated by unaltered ryanodine receptor binding properties. In conclusion, in isolated rat heart T(1)AM produces a cardioprotective effect which is mediated by a protein kinase C and K (ATP) (+) -dependent pathway and is probably linked to modulation of mitochondrial permeability transition and/or ischemic arrest time.

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Section: Discussionmentioning

confidence: 99%

Cardioprotective Effect of 3-Iodothyronamine in Perfused Rat Heart Subjected to Ischemia and Reperfusion

Frascarelli

Ghelardoni

Chiellini

et al. 2011

Cardiovasc Drugs Ther

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“…173,[175][176][177] In larger mammals, the PKCα isoform is most important for protection by IPC through activation of ecto 5′ nucleotidase and adenosine formation 178 and interaction/colocalization with sarcolemmal Cx 43. 179 In rodents, the PKCε isoform is most important for protection by IPC, 180,181 and PKCε is translocated to the mitochondria through a heat shock protein-dependent import, 182 where it activates mitochondrial K ATP channels during IPC 183 to increase ROS formation, which then further activate PKCε in a positive feedback loop. 184 PKCε is also translocated to the sarcoplasmic reticulum where it reduces calcium content.…”

Section: Protein Kinase Cmentioning

confidence: 99%

Molecular Basis of Cardioprotection

Heusch

2015

Circulation Research

713

409

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Abstract:Reperfusion is mandatory to salvage ischemic myocardium from infarction, but reperfusion per se contributes to injury and ultimate infarct size. Therefore, cardioprotection beyond that by timely reperfusion is needed to reduce infarct size and improve the prognosis of patients with acute myocardial infarction. The conditioning phenomena provide such cardioprotection, insofar as brief episodes of coronary occlusion/ reperfusion preceding (ischemic preconditioning) or following (ischemic postconditioning) sustained myocardial ischemia with reperfusion reduce infarct size. Even ischemia/reperfusion in organs remote from the heart provides cardioprotection (remote ischemic conditioning). The present review characterizes the signal transduction underlying the conditioning phenomena, including their physical and chemical triggers, intracellular signal transduction, and effector mechanisms, notably in the mitochondria. Cardioprotective signal transduction appears as a highly concerted spatiotemporal program. Although the translation of ischemic postconditioning and remote ischemic conditioning protocols to patients with acute myocardial infarction has been fairly successful, the pharmacological recruitment of cardioprotective signaling has been largely disappointing to date.

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“…Indeed, IPC initiates a complex cascade involving numerous kinases (protein kinase C, [15] tyrosine kinases [16,17] and MAP kinases [18]). Clearly activation of the serine/threonine protein kinase C during the IPC stimulus is necessary for cardioprotection [19,20] with the IPC stimulus in canine, [21] rat, [22] and rabbit [19] causing translocation of PKC-epsilon. Furthermore, mice deficient in PKC-epsilon or PKC-epsilon-Lck interaction lack cardioprotection [20,23].…”

Section: Discussionmentioning

confidence: 99%

“…Clearly activation of the serine/threonine protein kinase C during the IPC stimulus is necessary for cardioprotection [19,20] with the IPC stimulus in canine, [21] rat, [22] and rabbit [19] causing translocation of PKC-epsilon. Furthermore, mice deficient in PKC-epsilon or PKC-epsilon-Lck interaction lack cardioprotection [20,23]. One possible mechanism for the observed IPC resistance that has not been explored may involve a downregulation of PKC following the initial IPC stimulus.…”

Section: Discussionmentioning

confidence: 99%