The carboxyl-terminal cytoplasmic domain of the angiotensin II type 1 (AT(1)) receptor has recently been shown to interact with several classes of cytoplasmic proteins that regulate different aspects of AT(1) receptor...
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The carboxyl-terminal cytoplasmic domain of the angiotensin II type 1 (AT(1)) receptor has recently been shown to interact with several classes of cytoplasmic proteins that regulate different aspects of AT(1) receptor physiology. Employing yeast two-hybrid screening of a mouse kidney cDNA library with the carboxyl-terminal cytoplasmic domain of the murine AT(1a) receptor as a bait, we have isolated a novel protein with a predicted molecular mass of 18 kDa, which we have named ATRAP (for AT(1) receptor-associated protein). ATRAP interacts specifically with the carboxyl-terminal domain of the AT(1a) receptor but not with those of ansotensin II type 2 (AT(2)), m(3) muscarinic acetylcholine, bradykinin B-2, endothelin B, and beta(2)-adrenergic receptors, The mRNA of ATRAP was abundantly expressed in kidney, heart, and testis but was poorly expressed in lung, liver, spleen, and brain. The ATRAP-AT(1a) receptor association was confirmed by affinity chromatography, by specific co-immunoprecipitation of the two proteins, and by fluorescence microscopy, showing co-localization of these proteins in intact cells. Overexpression of ATRAP in COS-7 cells caused a marked inhibition of AT(1a) receptor-mediated activation of phospholipase C without affecting m(3) receptor-mediated activation. In conclusion, we have isolated a novel protein that interacts specifically with the carboxyl-terminal cytoplasmic domain of the AT(1a) receptor and affects AT(1a) receptor signaling.
Angiotensin II (AII) is a major determinant of arterial pressure and volume homeostasis, mainly because of its vascular action via the All type 1 receptor (AT1R), All has also been implicated in the development of car...
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Angiotensin II (AII) is a major determinant of arterial pressure and volume homeostasis, mainly because of its vascular action via the All type 1 receptor (AT1R), All has also been implicated in the development of cardiac hypertrophy because angiotensin I-converting enzyme inhibitors and AT1R antagonists prevent or regress ventricular hypertrophy in animal models and in human. However, because these treatments impede the action of All at cardiac as well as vascular levels, and reduce blood pressure, it has been difficult to determine whether AII action on the heart is direct or a consequence of pressure-overload. To determine whether AII can induce cardiac hypertrophy directly via myocardial AT1R in the absence of vascular changes, transgenic mice overexpressing the human AT1R under the control of the mouse alpha-myosin heavy chain promoter were generated. Cardiomyocyte-specific overexpression of AT1R induced, in basal conditions, morphologic changes of myocytes and nonmyocytes that mimic those observed during the development of cardiac hypertrophy in human and in other mammals. These mice displayed significant cardiac hypertrophy and remodeling with increased expression of ventricular atrial natriuretic factor and interstitial collagen deposition and died prematurely of heart failure. Neither the systolic blood pressure nor the heart rate were changed. The data demonstrate a direct myocardial role for AII in the development of cardiac hypertrophy and failure and provide a useful model to elucidate the mechanisms of action of AII in the pathogenesis of cardiac diseases.
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