MAP Kinase-Mediated and MLCK-Independent Phosphorylation of MLC20 in Smooth Muscle Cells

Deng, Maoxian; Deng, Lixia; Xue, Yarong

doi:10.5772/47732

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2024

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Cited by 2 publications

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“…ip3 se une a receptores específicos del retículo endoplásmico, produciendo la liberación de calcio (Ca 2+), aumentando la concentración del calcio citosólico ([Ca +2 ]i). este aumento de [Ca 2+ ]i junto a diacilglicerol activan a la proteína quinasa C (pKC), que fosforila proteínas específicas 23,24 (Figura 1). el tromboxano A 2 (txA 2 ) es un prostanoide inestable, metabolito del ácido araquidónico (AA) 25 .…”

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Mecanismos regulatorios del tono vascular pulmonar neonatal. Una perspectiva molecular

et al. 2017

Rev. chil. enferm. respir.

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Mecanismos regulatorios del tono vascular pulmonar neonatal. Una perspectiva molecular

et al. 2017

Rev. chil. enferm. respir.

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The novel ROCK2 selective inhibitor NRL-1049 preserves the blood-brain barrier after acute injury

Mulder,

Abbinanti,

Woller

et al. 2024

J Cereb Blood Flow Metab

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Endothelial blood-brain barrier (BBB) dysfunction is critical in the pathophysiology of brain injury. Rho-associated protein kinase (ROCK) activation disrupts BBB integrity in the injured brain. We aimed to test the efficacy of a novel ROCK2 inhibitor in preserving the BBB after acute brain injury. We characterized the molecular structure and pharmacodynamic and pharmacokinetic properties of a novel selective ROCK2 inhibitor, NRL-1049, and its first metabolite, 1-hydroxy-NRL-1049 (referred to as NRL-2017 hereon) and tested the efficacy of NRL-1049 on the BBB integrity in rodent models of acute brain injury. Our data show that NRL-1049 and NRL-2017 both inhibit ROCK activity and are 44-fold and 17-fold more selective towards ROCK2 than ROCK1, respectively. When tested in a mouse model of cortical cryoinjury, NRL-1049 significantly attenuated the increase in water content. Interestingly, 60% of the mice in the vehicle arm developed seizures within 2 hours after cryoinjury versus none in the NRL-1049 arm. In spontaneously hypertensive rats, NRL-1049 attenuated the dramatic surge in Evans Blue extravasation compared with the vehicle arm after transient middle cerebral artery occlusion. Hemorrhagic transformation was also reduced. We show that NRL-1049, a selective ROCK2 inhibitor, is a promising drug candidate to preserve the BBB after brain injury.

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MAP Kinase-Mediated and MLCK-Independent Phosphorylation of MLC20 in Smooth Muscle Cells

Cited by 2 publications

References 40 publications

Mecanismos regulatorios del tono vascular pulmonar neonatal. Una perspectiva molecular

Mecanismos regulatorios del tono vascular pulmonar neonatal. Una perspectiva molecular

The novel ROCK2 selective inhibitor NRL-1049 preserves the blood-brain barrier after acute injury

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