Activated Protein C Rescues the Retina from Ischemia-Induced Cell Death

Du, Zhao‐Jiang; Yamamoto, Tatsuyoshi; Ueda, Tomoko; Suzuki, Mihoko; Tano, Yasuo; Kamei, Motohiro

doi:10.1167/iovs.10-5557

Cited by 28 publications

(37 citation statements)

References 25 publications

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“…This is in line with the finding that in the retina, hypoxia promotes apoptosis and that caspase-3 mediates proapoptotic effects of hypoxia (Akopian et al 2000;Du et al 2011;Kaur et al 2008). In addition, in the ischemic rat retina, apoptosis is executed by caspase-3, whereas preventing caspase activation protects the retina against ischemia-induced damage (Katai and Yoshimura 1999).…”

Section: Apoptotic Signals and Octreotide Effectssupporting

confidence: 90%

“…In retinal explants, we determined the effect of hypoxia on caspase-3 activity used as apoptotic marker in retinal cells under hypoxic/ischemic conditions (Chen et al 2007;Du et al 2011;Tezel and Wax 1999) and the Bax/Bcl-2 ratio with an increase in the ratio indicating a high susceptibility of retinal cells to apoptosis (Nickells et al 2008). As shown in Fig.…”

Section: Apoptotic Signalsmentioning

confidence: 99%

“…In fact, in rodent models of oxygen-induced retinopathy (OIR), cell apoptosis has been observed in retinal layers (Akkoyun et al 2010;Dorfman et al 2011;Park et al 2010;Stevenson et al 2010). In this respect, hypoxia causes retinal cell loss through the involvement of caspases that play essential roles in apoptosis (Chen et al 2007;Du et al 2011;Tezel and Wax 1999). In addition, hypoxia upregulates the proapoptotic protein Bax, whereas it downregulates the antiapoptotic protein Bcl-2 in rat retinal cells (Tezel and Wax 1999).…”

Section: Introductionmentioning

confidence: 99%

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Protective role of somatostatin receptor 2 against retinal degeneration in response to hypoxia

Monte

Latina

Cupisti

et al. 2012

Naunyn-Schmiedeberg's Arch Pharmacol

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In mouse retinal explants, octreotide, a somatostatin [somatotropin release-inhibiting factor (SRIF)] receptor 2 (sst(2)) agonist, prevents the hypoxia-induced vascular endothelial growth factor upregulation. In mice with oxygen-induced retinopathy (OIR), a model of retinopathy of prematurity, either sst(2) overexpression or octreotide have been found to limit hypoxia-induced angiogenic processes. Here, we investigated whether sst(2) influences retinal degeneration in response to hypoxia in wild-type (WT), sst(1)- and sst(2)-knockout (KO) mice. In retinal explants, we determined the role of sst(2) on apoptotic signals. In control condition, caspase-3 activity and the Bax/Bcl-2 ratio were lower in sst(1)-KO than in WT, but higher in sst(2)-KO than in WT retinas. In all strains, a comparable increase in caspase-3 activity and the Bax/Bcl-2 ratio was observed after hypoxia. The hypoxia-induced increase in apoptotic signals was recovered by octreotide in both WT and sst(1)-KO retinas. To investigate the role of sst(2) on retinal function, we recorded electroretinogram (ERG) in response to light flashes in OIR mice. ERG responses did not differ between WT and KO mice with the exception of oscillatory potentials (OPs) which, in sst(1)-KO mice, displayed much larger amplitude. In all strains, hypoxia drastically reduced a-, b-waves and OPs. In both WT and sst(1)-KO mice, octreotide recovered a- and b-waves, but did not recover OPs in sst(1)-KO mice. Neither apoptotic signals nor ERG was affected by octreotide in sst(2)-KO mice. These results show that sst(2) may protect retinal cells from hypoxia, thus implementing the background to establish potential pharmacological targets based on sst(2) pharmacology.

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Section: Apoptotic Signals and Octreotide Effectssupporting

confidence: 90%

Section: Apoptotic Signalsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Protective role of somatostatin receptor 2 against retinal degeneration in response to hypoxia

Monte

Latina

Cupisti

et al. 2012

Naunyn-Schmiedeberg's Arch Pharmacol

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“…14,74,117 On the basis of preclinical data showing APC benefits for I/R injury to the brain, 64 Kamei and colleagues initiated ongoing open-label studies of wt-APC administered directly by injection into the eye for ischemic retinal injury, which appear promising 118 and should lead to double-blind studies to clarify the real benefits of APC therapy for the ischemic damage to the retina.…”

Section: Wt-apc: Studies Of Wound Healing and Ischemic Retinal Injurymentioning

confidence: 99%

Activated protein C: biased for translation

Griffin

Zloković

Mosnier

2015

Blood

226

320

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The homeostatic blood protease, activated protein C (APC), can function as (1) an antithrombotic on the basis of inactivation of clotting factors Va and VIIIa; (2) a cytoprotective on the basis of endothelial barrier stabilization and anti-inflammatory and antiapoptotic actions; and (3) a regenerative on the basis of stimulation of neurogenesis, angiogenesis, and wound healing. Pharmacologic therapies using recombinant human and murine APCs indicate that APC provides effective acute or chronic therapies for a strikingly diverse range of preclinical injury models. APC reduces the damage caused by the following: ischemia/reperfusion in brain, heart, and kidney; pulmonary, kidney, and gastrointestinal inflammation; sepsis; Ebola virus; diabetes; and total lethal body radiation. For these beneficial effects, APC alters cell signaling networks and gene expression profiles by activating protease-activated receptors 1 and 3. APC’s activation of these G protein–coupled receptors differs completely from thrombin’s activation mechanism due to biased signaling via either G proteins or β-arrestin-2. To reduce APC-associated bleeding risk, APC variants were engineered to lack >90% anticoagulant activity but retain normal cell signaling. Such a neuroprotective variant, 3K3A-APC (Lys191-193Ala), has advanced to clinical trials for ischemic stroke. A rich data set of preclinical knowledge provides a solid foundation for potential translation of APC variants to future novel therapies.

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“…Consistent with the stimulatory effects on cell growth, APC displays strong anti-apoptotic properties, both in vitro and in vivo, via the inhibition of pro-apoptotic factors, caspase-3, 8, 9 [30] and p53 [31], and upregulation of anti-apoptotic molecules, including endothelial nitric oxide synthase and Bcl-2 homologue [32]. …”

Section: Protective Effects Of Apc In Skinmentioning

confidence: 99%

Novel Functions of the Anticoagulant Activated Protein C in Maintaining Skin Barrier Integrity to Impact on Skin Disease

Xue

Jackson²

2015

Pathobiology

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The epidermis is the outermost skin layer and provides the first line of defence against the external environment. Keratinocytes are the most predominant cells in the epidermis and play a critical role in maintaining epidermal barrier function. When the barrier is disrupted any of a number of diseases, such as chronic wounds, psoriasis, pemphigus, atopic dermatitis or toxic epidermal necrolysis, can take hold. Activated protein C (APC) or its precursor, protein C, is abundantly expressed by skin epidermal keratinocytes and stimulates their proliferation and migration, and inhibits apoptosis and inflammation, leading to a healing phenotype. Importantly, APC also increases the barrier function of keratinocytes by promoting expression and cell-cell contact redistribution of tight junction proteins. These cytoprotective properties of APC on epidermal keratinocytes place it as an exciting new therapy for skin disorders associated with the disruption of barrier function and inflammation.

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Activated Protein C Rescues the Retina from Ischemia-Induced Cell Death

Abstract: APC can reduce ischemia-induced cytotoxicity both in vitro and in vivo via blocking the activation of caspase-3, -8, and -9. APC may be a promising candidate for protecting the retina from ischemia.

Cited by 28 publications

References 25 publications

Protective role of somatostatin receptor 2 against retinal degeneration in response to hypoxia

Protective role of somatostatin receptor 2 against retinal degeneration in response to hypoxia

Activated protein C: biased for translation

Novel Functions of the Anticoagulant Activated Protein C in Maintaining Skin Barrier Integrity to Impact on Skin Disease

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