scholarly journals Inhibition of Plasminogen Activator Inhibitor-1 Restores Skeletal Muscle Regeneration in Untreated Type 1 Diabetic Mice

Diabetes ◽  
2011 ◽  
Vol 60 (7) ◽  
pp. 1964-1972 ◽  
Author(s):  
M. P. Krause ◽  
J. Moradi ◽  
A. A. Nissar ◽  
M. C. Riddell ◽  
T. J. Hawke
Keyword(s):  
Skeletal Muscle ◽  
Plasminogen Activator ◽  
Muscle Regeneration ◽  
Plasminogen Activator Inhibitor ◽  
Skeletal Muscle Regeneration ◽  
Diabetic Mice ◽  
Plasminogen Activator Inhibitor 1 ◽  
Activator Inhibitor

Mice deficient in plasminogen activator inhibitor-1 have improved skeletal muscle regeneration

2005 ◽  
Vol 289 (1) ◽  
pp. C217-C223 ◽  
Author(s):  
Timothy J. Koh ◽  
Scott C. Bryer ◽  
Augustina M. Pucci ◽  
Thomas H. Sisson
Keyword(s):  
Skeletal Muscle ◽  
Plasminogen Activator ◽  
Muscle Regeneration ◽  
Plasminogen Activator Inhibitor ◽  
Skeletal Muscle Regeneration ◽  
Wild Type ◽  
Plasminogen Activator Inhibitor 1 ◽  
Activator Inhibitor ◽  
Pai 1 ◽  
Macrophage Accumulation

Skeletal muscle possesses a remarkable capacity for regeneration. Although the regulation of this process at the molecular level remains largely undefined, the plasminogen system appears to play a critical role. Specifically, mice deficient in either urokinase-type plasminogen activator (uPA−/− mice) or plasminogen demonstrate markedly impaired muscle regeneration after injury. In the present study, we tested the hypothesis that loss of the primary inhibitor of uPA, plasminogen activator inhibitor-1 (PAI-1), would improve muscle regeneration. Repair of the extensor digitorum longus muscle was assessed after cardiotoxin injury in wild-type, uPA−/−, and PAI-1-deficient (PAI-1−/−) mice. As expected, there was no uPA activity in the injured muscles of uPA−/− mice, and muscles from these transgenic animals demonstrated impaired regeneration. On the other hand, uPA activity was increased in injured muscle from PAI-1−/− mice to a greater extent than in wild-type controls. Furthermore, PAI-1−/− mice demonstrated increased expression of MyoD and developmental myosin after injury as well as accelerated recovery of muscle morphology, protein levels, and muscle force compared with wild-type animals. The injured muscles of PAI-1-null mice also demonstrated increased macrophage accumulation, contrasting with impaired macrophage accumulation in uPA-deficient mice. The extent of macrophage accumulation correlated with both the clearance of protein after injury and the efficiency of regeneration. Taken together, these results indicate that PAI-1 deficiency promotes muscle regeneration, and this protease inhibitor represents a therapeutic target for enhancing muscle regeneration.

scholarly journals Statin Therapy Negatively Impacts Skeletal Muscle Regeneration and Cutaneous Wound Repair in Type 1 Diabetic Mice

2017 ◽  
Vol 8 ◽  
Author(s):  
Irena A. Rebalka ◽  
Andrew W. Cao ◽  
Matthew J. Raleigh ◽  
Brandyn D. Henriksbo ◽  
Samantha K. Coleman ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Statin Therapy ◽  
Muscle Regeneration ◽  
Wound Repair ◽  
Skeletal Muscle Regeneration ◽  
Diabetic Mice ◽  
Cutaneous Wound

scholarly journals Plasminogen activator inhibitor-1 expression is regulated by the angiotensin type 1 receptor in vivo1

2000 ◽  
Vol 58 (1) ◽  
pp. 251-259 ◽  
Author(s):  
Shinya Nakamura ◽  
Ikuko Nakamura ◽  
Lijun Ma ◽  
Douglas E. Vaughan ◽  
Agnes B. Fogo
Keyword(s):  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Plasminogen Activator Inhibitor 1 ◽  
Activator Inhibitor ◽  
Angiotensin Type

scholarly journals Characterization of Signal Transduction Pathway in Neurotropic Action of Angiotensin II in Brain Neurons

Endocrinology ◽  
2001 ◽  
Vol 142 (8) ◽  
pp. 3502-3511 ◽  
Author(s):  
Hong Yang ◽  
Xiangyu Wang ◽  
Mohan K. Raizada
Keyword(s):  
Angiotensin Ii ◽  
Plasminogen Activator ◽  
Signaling Pathway ◽  
Plasminogen Activator Inhibitor ◽  
Neurotropic Activity ◽  
Plasminogen Activator Inhibitor 1 ◽  
P70s6 Kinase ◽  
Activator Inhibitor ◽  
Angiotensin Type

Abstract Interaction of angiotensin II with the neuronal angiotensin type 1 receptor stimulates the PI3K signaling pathway. Our objective in this study was to investigate the hypothesis that the PI3K cascade regulates the neurotropic actions of angiotensin II in rat brain neurons. We followed growth associated protein-43 expression and neurite extension as markers of neurotropic activity. Angiotensin II, through its interaction with the angiotensin type 1 receptor, increased growth associated protein-43 expression and neurite extension. These effects were abolished by pretreatment of neurons with wortmannin and rapamycin, but not by PD 98059. Antisense oligonucleotides specific for p70S6 kinase also inhibited angiotensin II-stimulated neurotropic activity. These data confirm the involvement of PI3K and p70S6 kinase in angiotensin II-mediated neurotropic action. Further support for this was provided by the observation that angiotensin II caused a time-dependent stimulation of p70S6 kinase by an angiotensin type 1 receptor-mediated process. We also found that the neurotropic actions of angiotensin II are mediated by plasminogen activator inhibitor-1. Evidence for this includes 1) angiotensin II-stimulated neuronal plasminogen activator inhibitor-1 gene expression, 2) potent neurotropic action of exogenous plasminogen activator inhibitor-1, and 3) inhibitory neurotropic effect of angiotensin II by antisense oligonucleotide-mediated depletion of plasminogen activator inhibitor-1. Finally, we found that the neurotropic action of plasminogen activator inhibitor-1 is not blocked by either angiotensin type 1 receptor antagonist or inhibitors of PI3K or p70S6 kinase, indicating that the plasminogen activator inhibitor-1 step is downstream from the p70S6 kinase. These observations demonstrate that angiotensin II is a neurotropic hormone that engages a distinct PI3K-p70S6 kinase-plasminogen activator inhibitor-1 signaling pathway for this action.

scholarly journals Angiotensin type 2 receptor actions contribute to angiotensin type 1 receptor blocker effects on kidney fibrosis

2010 ◽  
Vol 298 (3) ◽  
pp. F683-F691 ◽  
Author(s):  
Takashi Naito ◽  
Li-Jun Ma ◽  
Haichun Yang ◽  
Yiqin Zuo ◽  
Yiwei Tang ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Angiotensin Ii ◽  
Kidney Disease ◽  
Receptor Antagonist ◽  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Plasminogen Activator Inhibitor 1 ◽  
Activator Inhibitor ◽  
Angiotensin Type

Angiotensin type 1 (AT1) receptor blocker (ARB) ameliorates progression of chronic kidney disease. Whether this protection is due solely to blockade of AT1, or whether diversion of angiotensin II from the AT1 to the available AT2 receptor, thus potentially enhancing AT2 receptor effects, is not known. We therefore investigated the role of AT2 receptor in ARB-induced treatment effects in chronic kidney disease. Adult rats underwent 5/6 nephrectomy. Glomerulosclerosis was assessed by renal biopsy 8 wk later, and rats were divided into four groups with equivalent glomerulosclerosis: no further treatment, ARB, AT2 receptor antagonist, or combination. By week 12 after nephrectomy, systolic blood pressure was decreased in all treatment groups, but proteinuria was decreased only with ARB. Glomerulosclerosis increased significantly in AT2 receptor antagonist vs. ARB. Kidney cortical collagen content was decreased in ARB, but increased in untreated 5/6 nephrectomy, AT2 receptor antagonist, and combined groups. Glomerular cell proliferation increased in both untreated 5/6 nephrectomy and AT2 receptor antagonist vs. ARB, and phospho-Erk2 was increased by AT2 receptor antagonist. Plasminogen activator inhibitor-1 mRNA and protein were increased at 12 wk by AT2 receptor antagonist in contrast to decrease with ARB. Podocyte injury is a key component of glomerulosclerosis. We therefore assessed effects of AT1 vs. AT2 blockade on podocytes and interaction with plasminogen activator inhibitor-1. Cultured wild-type podocytes, but not plasminogen activator inhibitor-1 knockout, responded to angiotensin II with increased collagen, an effect that was completely blocked by ARB with lesser effect of AT2 receptor antagonist. We conclude that the benefical effects on glomerular injury achieved with ARB are contributed to not only by blockade of the AT1 receptor, but also by increasing angiotensin effects transduced through the AT2 receptor.

Plasminogen activator inhibitor-1 is associated with coronary artery calcium in Type 1 diabetes

2009 ◽  
Vol 23 (6) ◽  
pp. 387-393 ◽  
Author(s):  
Katherine A. Pratte ◽  
Anna E. Barón ◽  
Lorraine G. Ogden ◽  
Kathryn L. Hassell ◽  
Marian Rewers ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Coronary Artery ◽  
Plasminogen Activator ◽  
Coronary Artery Calcium ◽  
Plasminogen Activator Inhibitor ◽  
Plasminogen Activator Inhibitor 1 ◽  
Activator Inhibitor
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