Anti-Ischemic Effect of a Novel Cardioprotective Agent, JTV519, Is Mediated Through Specific Activation of δ-Isoform of Protein Kinase C in Rat Ventricular Myocardium

Inagaki, Kenji; Kihara, Yasuki; Hayashida, Wataru; Izumi, Toshiaki; Iwanaga, Yoshitaka; Yoneda, Tomohiro; Takeuchi, Yuzo; Suyama, Katsuo; Muso, Eri; Sasayama, Shígetake

doi:10.1161/01.cir.101.7.797

Cited by 62 publications

(30 citation statements)

References 23 publications

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“…Carbachol and PMA also caused an increase in PKC-␣ levels in the cytosol, followed by its increase in membrane fractions (12). Inagaki et al (6) showed that a novel drug, JTV519, has protective effect against Ca 2ϩ overload-induced myocardial injury and provides an anti-ischemic effect via specific activation of PKC-␦ in rat hearts. Miyawaki and Ashraf (18) demonstrated that high-calcium preconditioning evoked the translocation of PKC-␣ and PKC-␦ to the cell membrane.…”

Section: Discussionmentioning

confidence: 99%

Protein kinase C plays an essential role in sildenafil-induced cardioprotection in rabbits

Das

Ockaili

Salloum

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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Sildenafil citrate (Viagra) is the most widely used pharmacological drug for treating erectile dysfunction in men. It has potent cardioprotective effects against ischemia-reperfusion injury via nitric oxide and opening of mitochondrial ATP-sensitive K+ channels. We further investigated the role of protein kinase C (PKC)-dependent signaling pathway in sildenafil-induced cardioprotection. Rabbits were treated (orally) with sildenafil citrate (1.4 mg/kg) 30 min before index ischemia for 30 min and reperfusion for 3 h. The PKC inhibitor chelerythrine (5 mg/kg iv) was given 5 min before sildenafil. Infarct size (% of risk area) reduced from 33.65 ± 2.17 in the vehicle (saline) group to 15.07 ± 0.63 in sildenafil-treated groups, a 45% reduction compared with vehicle (mean ± SE, P < 0.05). Chelerythrine abolished sildenafil-induced protection, as demonstrated by increase in infarct size to 31.14 ± 2.4 ( P < 0.05). Chelerythrine alone had an infarct size of 33.5 ± 2.5, which was not significantly different compared with DMSO-treated group (36.8 ± 1.7, P > 0.05). Western blot analysis demonstrated translocation of PKC-α, -θ, and -δ isoforms from cytosol to membrane after treatment with sildenafil. However, no change in the PKC-β and -ϵ isoforms was observed. These data provide direct evidence of an essential role of PKC, and potentially PKC-α, -θ, and -δ, in sildenafil-induced cardioprotection in the rabbit heart.

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Section: Discussionmentioning

confidence: 99%

Protein kinase C plays an essential role in sildenafil-induced cardioprotection in rabbits

Das

Ockaili

Salloum

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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“…31 Furthermore, the anti-ischemic effect of a novel cardioprotective agent JTC519 appears to be mediated through the specific activation of PKC-␦. 32 Thus, the stimulation of novel PKCs may be essential for the development of protection against hypoxic injury in different tissues. Although PKC stimulation in preconditioned myocardium largely relies on adenosine A 1 stimulation, 25 a possible functional link between novel PKCs and A 2A receptors is suggested by the observation that PCK-␦ and -are involved in the modulation of adenylate cyclase activity in rat pheochromocytoma PC12 cells treated with CGS21680.…”

Section: Discussionmentioning

confidence: 99%

Signal Pathway Involved in the Development of Hypoxic Preconditioning in Rat Hepatocytes

Carini¹,

Cesaris²,

Splendore³

et al. 2001

Hepatology

102

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Ischemic preconditioning improves liver resistance to hypoxia and reduces reperfusion injury following transplantation. However, the intracellular signals that mediate the development of liver hypoxic preconditioning are largely unknown. We have investigated the signal pathway leading to preconditioning in freshly isolated rat hepatocytes. Hepatocytes were preconditioned by 10-minute incubation under hypoxic conditions followed by 10 minutes of reoxygenation and subsequently exposed to 90 minutes of hypoxia. Preconditioning reduced hepatocyte killing by hypoxia by about 35%. A similar protection was also obtained by preincubation with chloro-adenosine or with A 2A -adenosine receptor agonist CGS21680, whereas A 1 -adenosine receptor agonist N-phenyl-isopropyladenosine (R-PIA) was inactive. Conversely, the development of preconditioning was blocked by A 2 -receptor antagonist 3,7-dimethyl-1-propargylxanthine (DMPX), but not by A 1 -receptor antagonist 8-cyclopenthyl-1,3-dipropylxanthine (DPCPX). In either preconditioned or CGS21680-treated hepatocytes a selective activation of ␦ and protein kinase C (PKC) isoforms was also evident. Inhibition of heterotrimeric G i protein or of phospholypase C by, respectively, pertussis toxin or U73122, prevented PKC activation as well as the development of preconditioning. MEK inhibitor PD98509 did not interfere with preconditioning that was instead blocked by p38 MAP kinase inhibitor SB203580. The direct activation of p38 MAPK by anisomycin A mimicked the protection against hypoxic injury given by preconditioning. Consistently, an increased phosphorylation of p38 MAPK was observed in preconditioned or CGS21680-treated hepatocytes, and this effect was abolished by PKC-blocker, chelerythrine. We propose that a signal pathway involving A 2A -adenosine receptors, G i -proteins, phospholypase C, ␦-and -PKCs, and p38 MAPK, is responsible for the deve- The term ischemic preconditioning refers to the resistance to ischemic injury acquired by tissue following one or more brief periods of ischemia followed by reperfusion. 1,2 Ischemic preconditioning was first described in the myocardium, 1 but has been shown in several other organs, including the brain, the skeletal muscles, and the small intestine. 3 In the heart, ischemic preconditioning occurs in 2 phases: an early phase (early preconditioning) that immediately follows the transient hypoxia and lasts 2 to 3 hours and a late phase (late preconditioning), which begins 12 to 24 hours from the transient ischemia and lasts for about 3 to 4 days. 3 Recent studies have shown that the same phenomenon could also be observed in the liver. [4][5][6][7][8][9][10] In particular, 10-minute interruption of liver blood supply in anesthetized rats followed by 10 minutes of reperfusion reduces transaminases released during a subsequent 90-minute period of ischemia and 90-minute reoxygenation. 5 A similar effect has also been observed in steatosic livers following heat shock preconditioning. 7 Furthermore, ischemic preconditioning before cold preserva...

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“…-overload during the first few minutes of ischemia (30), whereas diltiazem treatment during reperfusion failed to reduce myocardial injury (8,9). Accordingly, they support the hypothesis that Ca 2+ influx via NCX rather than Ca…”

Section: +mentioning

confidence: 53%

Caldaret, an Intracellular Ca2+ Handling Modulator, Limits Infarct Size of Reperfused Canine Heart

Kawasumi¹,

Satoh²,

Kitada³

2007

J Pharmacol Sci

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Abstract. The cardioprotective effect of caldaret, a novel intracellular Ca 2+ handling modulator that acts through reverse-mode Na + / Ca 2+ exchanger inhibition and potential sarcoplasmic reticulum (SR) Ca 2+ uptake enhancement, against reperfusion injury was investigated. We employed a canine model of myocardial infarction induced by 90-min occlusion of left circumflex (LCX) coronary artery followed by 4 h of reperfusion. Intravenously infused caldaret (3 or 30 µg / kg per hour) for 30 min at LCX-reperfusion markedly reduced infarct size (by 51.3% or 71.9%, respectively). This cardioprotection was accompanied by an acceleration of left ventricular (LV) contraction and relaxation during reperfusion, but not by an increase in ischemic regional transmural myocardial blood flow (TMBF) or endocardial / epicardial blood flow ratio (Endo / Epi ratio) or a reduction in double-product throughout the protocol. Diltiazem (2000 µg / kg per hour) also reduced infarct size (by 36.1%), but unlike caldaret, was accompanied by the significant increase in Endo / Epi ratio in the ischemic region and decrease in double-product. There were significant inverse relationships between infarct size and ischemic regional TMBF in all groups. Caldaret, but not diltiazem shifted the regression line downward with a flatter slope. These results suggest that the amelioration of intracellular Ca 2+ handling dysfunction achieved by caldaret leads to cardioprotective effects against reperfusion injury following prolonged ischemia.

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Anti-Ischemic Effect of a Novel Cardioprotective Agent, JTV519, Is Mediated Through Specific Activation of δ-Isoform of Protein Kinase C in Rat Ventricular Myocardium

Cited by 62 publications

References 23 publications

Protein kinase C plays an essential role in sildenafil-induced cardioprotection in rabbits

Protein kinase C plays an essential role in sildenafil-induced cardioprotection in rabbits

Signal Pathway Involved in the Development of Hypoxic Preconditioning in Rat Hepatocytes

Caldaret, an Intracellular Ca2+ Handling Modulator, Limits Infarct Size of Reperfused Canine Heart

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