| Budget Amount *help |
¥14,800,000 (Direct Cost: ¥14,800,000)
Fiscal Year 2000: ¥4,900,000 (Direct Cost: ¥4,900,000)
Fiscal Year 1999: ¥9,900,000 (Direct Cost: ¥9,900,000)
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| Research Abstract |
Due to the discovery of nonpeptidic ligands the receptors for angiotensin (Angl II are classified into two subtypes (AT1-R and AT2-R). AT1-R. mediates most of the cardiovascular actions of Ang II. AT2-R is expressed at very high levels in the developing fetlrs. Its expression is vefy low in the cardiovascular system of the adult. The expression of AT2-R can be modulated by pathological states associated with tissue remodeling or inflaimmation. In failing hearts or neointima fonnation after vascular injury, AT2-R is re-expressed in cells proliferating in interstitial regions or neointima and exerts an inhibitory effect on Ang II-induced mitogen signals or synthesis of extracellular matrix proteins, resulting in attenuation of the tissue remodeling. An extreme form of cell growth inhibition ends in programmed cell death, and this process, which is initiated by the withdrawal of growth factors, is also enhanced by AT2-R. Cardiac myocyte- or vascular smooth muscle-specific mice that overexpress AT2-R display an inhibition of Ang II-induced chronotropic or pressor actions, suggesting the role of AT2-R on the activity of cardiac pacemaker cells and the maintenance of vascular resistance. AT2-R also activates the kinin/nitric. oxide/cGMP system in the cardiovascular and renal systems, restnlting in AT2-R-mediated cardioprotection, vasodilation and pressure natriuresis. These effects, transmitted by AT2-R, are mairily exerted by stimulation of protein tyrosine or serine/threonine phosphatases in a Gi-protein- dependent manner. The expression level of AT2-R is much higher in human hearts than in rodept hearts, and the AT2-R-mediated actions are likely enhanced, especially by clinical application of AT1-R antagonists. Thus, in this review, the regtilation of AT2-R expression, its cellular localization, its pathological role in cardiovascular and kidney ciseases, and phamlacotherapeutic effects of AT2-R stimulation are discussed.
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