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Role of the RhoA/Rho-kinase pathway in the regulation of pulmonary vasoconstrictor function

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Calcium is the major intracellular messenger that triggers smooth muscle contraction. The study of calcium-binding proteins, such as calmodulin and its downstream effectors, reveals critical regulation of smooth muscle contraction by protein kinases and phosphatases. Moreover, the small GTP-binding protein RhoA and its downstream effector protein, Rho-kinase, have been shown to play a novel role in the regulation of smooth muscle contraction. Studies have shown that the activation of Rho-kinase is involved in the development of endothelial dysfunction, inflammation, restenosis, and increased vascular tone in a number of cardiovascular disorders. Because inhibitors of this pathway promote vasodilation independent of the mechanism that increases vasoconstrictor tone, it is our hypothesis that Rho-kinase is constitutively active in regulating vasoconstrictor tone in the pulmonary and systemic vascular beds. Studies in the literature suggest that the RhoA/Rho-kinase pathway has an important role in the pathogenesis of pulmonary hypertension.

Le calcium est le principal messager intracellulaire qui déclenche la contraction du muscle lisse. L’examen des protéines liant le calcium, telles que la calmoduline et ses effecteurs en aval, met en lumière le rôle crucial des protéines kinases et phosphatases dans la régulation de la contraction des muscles lisses. De plus, on a démontré que la petite protéine liant le GTP, RhoA, ainsi que sa protéine effectrice en aval, Rho-kinase, jouent aussi un rôle dans la régulation de la contraction de ces muscles. Des études ont montré que l’activation de la Rho-kinase est impliquée dans le développement du dysfonctionnement endothélial, de l’inflammation, de la resténose, ainsi que dans l’augmentation du tonus vasculaire dans un grand nombre de maladies cardiovasculaires. Nous émettons l’hypothèse que la Rho-kinase est constitutivement active dans la régulation du tonus vasoconstricteur dans les lits vasculaires pulmonaires et systémiques, étant donné que les inhibiteurs de cette voie favorisent une vasodilatation indépendamment du mécanisme qui augmente le tonus vasoconstricteur. Les études dans la littérature donnent à penser que la voie RhoA/Rho-kinase joue un rôle important dans la pathogenèse de l’hypertension pulmonaire.

Document Type: Research Article

Publication date: January 1, 2010

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