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Rho-Associated Kinases in Cerebrovascular Disease
Introduction
More than two decades after their discovery, Rho-associated kinase (ROCK) is at the center stage of therapeutic development in many diverse diseases ranging from cardiovascular to neurological, metabolic, and ocular disorders. Because ROCK activity is pivotal in the regulation of numerous processes in virtually all cell types, the therapeutic indications have been wide ranging and growing. It is well established that upregulation of ROCK activity is a central mechanism contributing to vascular dysfunction in chronic hypertension, hyperlipidemia, type 1 and 2 diabetes, and atherosclerosis, as chronic vascular risk factors. ROCK inhibition lowers the arterial blood pressure, prevents cardiac hypertrophy in disease models, and inhibits the development of atherosclerosis. As such, it has found a broad range of potential cardiovascular indications for development. ROCK inhibition has a multitude of pleiotropic effects converging to provide additive or synergistic benefits, including antiinflammatory, antiplatelet, antiatherosclerotic, vasodilator, antiapoptotic, and axon growth promoting effects, all of which are predicted to be beneficial in cerebrovascular diseases . Indeed, ROCK inhibition is in part responsible for the beneficial effects of statins, which inhibit the production of isoprenoid building blocks of cholesterol that are also critical for posttranslational modification, subcellular localization, and function of Rho subfamily of small-molecular-weight monomeric GTPases, the immediate upstream regulators of ROCK function.
Rho-Associated Kinases
The Rho-associated kinases 1 (aka ROKβ, p160ROCK, ROCK1, ROCK I) and 2 (aka ROKα, ROCK2, ROCK II) are ∼160 kDa serine/threonine kinases that are among the downstream effectors of the small GTPase RhoA. The Rho/ROCK pathway acts as a molecular switch. Activated when bound to GTP-Rho, ROCK regulates numerous processes involving cytoskeletal rearrangement, such as activation, adhesion and aggregation of platelets, leukocyte migration, cell motility and proliferation, and smooth muscle contraction. The two ROCK isoforms show 65% sequence homology (58% in the Rho-binding domain and 92% in the kinase domain). Both ROCK1 and ROCK2 are expressed ubiquitously throughout the tissues from early embryonic development to adulthood. However, their subcellular localizations, upstream regulators, and tissue expression patterns differ. ROCK2 is expressed highest in the brain, muscle, and heart, whereas ROCK1 is abundantly expressed in the lung, liver, thymus, kidney, testis, spleen, and leukocytes . ROCK1 is expressed at low levels in the brain, predominantly in glial cells and not in neurons. Moreover, there is evidence suggesting that ROCK1 and ROCK2 serve different functions in different cell types and molecular pathways. Unfortunately, genetic global homozygous deletion of either ROCK isoform is embryonic or perinatal lethal albeit via different mechanisms , but they can to some extent also compensate for loss of each other’s activity.
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