Abstract-The development of left ventricular hypertrophy (LVH) in subjects with hypertrophic cardiomyopathy (HCM) is variable, suggesting a role for modifying factors such as angiotensin II. We investigated whether the angiotensin II type 1 receptor (AT 1 -R) A/C 1166 polymorphism, the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism, and/or plasma renin influence LVH in HCM. Left ventricular mass index (LVMI) and interventricular septal thickness were determined by 2-dimensional echocardiography in 104 genetically independent subjects with HCM. Extent of hypertrophy was quantified by a point score (Wigle score). Plasma prorenin, renin, and ACE were measured by immunoradiometric or fluorometric assays, and ACE and AT 1 -R genotyping were performed by polymerase chain reactions. The ACE D allele did not affect any of the measured parameters except plasma ACE (PϽ0.04). LVMI was higher (PϽ0.05) in patients carrying the AT 1 -R C allele (190Ϯ8.3 g/m 2 ) than in AA homozygotes (168Ϯ7.2 g/m 2 ), and similar patterns were observed for interventricular septal thickness (23.0Ϯ0.7 versus 21.6Ϯ0.7 mm) and Wigle score (7.0Ϯ0.3 versus 6.3Ϯ0.3). Plasma renin was higher (Pϭ0.05) in carriers of the C allele than in AA homozygotes. Multivariate regression analysis, however, revealed no independent role for renin in the prediction of LVMI. Plasma prorenin and ACE were not affected by the AT 1 -R A/C 1166 polymorphism, nor did the ACE and AT 1 -R polymorphisms interact with regard to any of the measured parameters. We conclude that the AT 1 -R C
Activation of the Ras proto-oncogene contributes in general to mitogenic activation of cells.We show here that epidermal growth factor (EGF) stimulates Ras . GTP formation very efficiently in a variety of cell lines expressing endogenous EGF receptors only. Maximal activation of the receptor converts up to 65% of cellular p2lras from the GDP form into the active GTPbound state. This efficient activation occurs also in cultured primary human fibroblasts. Maximal insulin-induced Ras . GTP formation is less but in cells overexpressing the insulin receptor a similar high response of Ras . GTP formation is observed after insulin stimulation.Not only the efficiency but also the kinetics by which the EGF and insulin receptors stimulate Ras . GTP formation are quite distinct. In the Rat-1-derived cell line, H13IR2000, overexpressing both p21Ha-ras and the insulin receptor, the activated insulin receptor generates approximately 1 mol Ras . GTP/mol activated insulin receptor. The activated EGF receptor amplifies the signal, resulting in the activation of approximately 40 mol p2lras/mol receptor.Moreover, EGF-stimulated generation of Ras . GTP is transient with a maximum after 2 min of hormone stimulation and &minishes to near basal levels within 1 h whereas the insulin-induced Ras . GTP levels are maximal at 5-10 min and decline only slowly to half-maximal in 1 h.Desensitization of the EGF pathway by prolonged EGF stimulation, prevents subsequent stimulation of Ras . GTP formation by newly added EGF but not by insulin. Vice versa, in cells preincubated with insulin for 1 h, EGF stimulates Ras . GTP formation to near maximal values. These observations indicate that desensitization by prolonged hormone incubation does not involve inactivation of common signaling intermediates but rather components, specific for each pathway, like the particular receptors. The rapid down regulation of EGF receptors compared to insulin receptors corroborate this possibility.The observed high potency of EGF receptors to generate Ras . GTP may explain the, in general, stronger mitogenic activity of EGF compared to insulin.In human tumors, one of the genes which is found frequently to be mutated is the proto-oncogene ras. It encodes a small protein of 21 kDa (p2lras) belonging to a large family of Ras-like proteins [l]. Members of this family have been found throughout the eukaryotic kingdom. Ras proteins participate in very different processes like mitogenic responses, maturation, differentiation and mating signals [2 -71. The p2lras protein has guanine nucleotide binding properties. When GDP is bound, p2lras is inactive and when GDP is exchanged for GTP the protein is activated. Mutations which keep p2lras stabilized in the active GTP-bound state are often tumorigenic 18, 91.The cycling of wild-type p2lras molecules between the active GTP-bound form and the inactive GDP-bound form seems to involve several processes. p2lras has an intrinsic low GTPase activity and thus can reverse its active state into the inactive one. However, cellular protei...
Regional Ang I to Ang II conversion does not parallel the previously described D allele-related differences in ACE concentration, suggesting that effects other than enhanced conversion may underlie the reported associations between the D allele and various cardiovascular diseases.
Activated receptors with a tyrosine kinase activity induce a variety of responses like changes in the differentiation and mitogenic status of cells. These responses are mediated in part by p2lras. Some of these activated receptors induce in certain cell types a pronounced, but transient, increase in RasOGTP. We have stimulated cells with insulin, epidermal growth factor (EGF), and fetal calf serum (FCS), and the mitogenic response, as reflected by stimulation of [ 3H] thymidine incorporation, was compared with the magnitude of the transient increase in RasOGTP levels. Cell lines were used that expressed both physiological and elevated numbers of p2lras and receptors for insulin and EGF, respectively. In all the examined cell lines 9% FCS did not induce a marked increase in Ras-GTP despite its high mitogenic potency. Pronounced increases in Ras-GTP levels were observed in insulin-stimulated C H O cells which overexpress insulin receptors whereas in the parental C H O cells only a small increase is seen. Insulin (1 pM The ras protooncogenes encode small guanine nucleotide binding proteins with molecular masses of approximately 2lkDa (Barbacid, 1987). P2lras is active when complexed to GTP. It has a slow intrinsic GTPase activity that converts Ras.GTP into inactive RasSGDP. This activity is enhanced by cellular proteins like pl20-GAP' and NF1-GAP (McCormick, 1992). Activation of p2lras requires exchange of bound GDP for GTP (Randazzo et al., 1992). A variety of proteins, regulating this exchange, have been identified (West et al., 1990;Downward et al., 1990b
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