2009
DOI: 10.1172/jci38476
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Abstract: Activated protein C (APC) is a signaling protease with anticoagulant activity. Here, we have used mice expressing a mutation in superoxide dismutase-1 (SOD1) that is linked to amyotrophic lateral sclerosis (ALS) to show that administration of APC or APC analogs with reduced anticoagulant activity after disease onset slows disease progression and extends survival. A proteolytically inactive form of APC with reduced anticoagulant activity provided no benefit. APC crossed the blood-spinal cord barrier in mice via… Show more

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Cited by 130 publications
(202 citation statements)
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“…Hitherto, studies exploring vascular disease have focused on the effect of aPC or p66 Shc in endothelial cells (26), but the effect of aPC on p66 Shc in podocytes reported here implies that perivascular cells should be equally considered and evaluated. Along this line, a potential role for aPC outside the vascular compartment (in microglia and astrocytes) has been reported in a murine model of amyotrophic lateral sclerosis (4). Considering the role of p66 Shc in both endothelial cells and podocytes, we suggest that mechanistic evaluations and therapeutic developments should not be limited to targeting endothelial cells, but should involve podocytes and, more generally, pericytes as well.…”
Section: Discussionmentioning
confidence: 65%
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“…Hitherto, studies exploring vascular disease have focused on the effect of aPC or p66 Shc in endothelial cells (26), but the effect of aPC on p66 Shc in podocytes reported here implies that perivascular cells should be equally considered and evaluated. Along this line, a potential role for aPC outside the vascular compartment (in microglia and astrocytes) has been reported in a murine model of amyotrophic lateral sclerosis (4). Considering the role of p66 Shc in both endothelial cells and podocytes, we suggest that mechanistic evaluations and therapeutic developments should not be limited to targeting endothelial cells, but should involve podocytes and, more generally, pericytes as well.…”
Section: Discussionmentioning
confidence: 65%
“…Epigenetic control of gene expression may explain the profound effects of intermittently administered exogenous aPC in various animal models despite its half-life of only ∼25 min (4,6). aPC suppressed expression of p66 Shc at concentrations as low as 2 nM, which is ∼100-fold lower than the concentrations of aPC previously used by Yamaji et al (5) to study the antioxidant H3 acetylation within the p66 Shc promoter is induced by glucose and prevented by aPC (2 nM).…”
Section: Discussionmentioning
confidence: 87%
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“…26 Double transgenic animals still had about 50% greater IgG leakages compared with wild-type mice most likely because hSOD1 G37R expression in cells surrounding the endothelium contribute to the pathology in this multifactorial disease. Nevertheless, as in our study primary endothelial cells were selected in the presence of puromycin, our results strongly indicate that the expression of hSOD1 G93A in endothelial cells results in the impaired integrity.…”
Section: Discussionmentioning
confidence: 98%
“…As the immunohistochemical analysis of the SOD G93A mice is not the primary scope of this article please consult the original publication in which these transgenic mice have been characterized and more recent ones which study therapeutic approaches for further reference 1,5,6 . If therapeutic effects shall be differentiated on the immunohistological level clearly defined quantitative evaluation algorithms should be applied supported by a stereological software (for example see 7 ).…”
Section: Representative Resultsmentioning
confidence: 99%