ABSTRACT
PTEN, a tumor suppressor gene, is frequently mutated in a variety of human tumors. In mice, monoallelic inactivation of this gene predisposes animals to neoplasia of multiple organs. Interestingly, Pten heterozygous mice develop bilateral hyperplasia of the adrenal medulla. In this report we demonstrate that these neoplasms are hormonally active pheochromocytomas that secrete increased amounts of bioactive catecholamines: norepinephrine and epinephrine. To test a possibility that PTEN might be one of the genes responsible for human sporadic pheochromocytoma, we performed mutation analysis of DNA obtained from tumors of 29 patients. However, direct sequencing of all nine exons of the PTEN gene, including the splice junctions, revealed no mutations. Examination of protein expression by immunohistochemistry using 8 normal adrenals and 11 sporadic pheochromocytomas showed no decrease in the PTEN protein expression in the tumor tissue, but upregulation of insulin-like growth factor II, a peptide implicated in growth of adrenal tissue, was observed in four cases (36%).
Subject(s)
Adrenal Gland Neoplasms/genetics , Mutation , PTEN Phosphohydrolase/genetics , Pheochromocytoma/genetics , Animals , Base Sequence , DNA Primers , Immunohistochemistry , MiceABSTRACT
BACKGROUND: There are numerous data indicating a significant role of the sympathoadrenal system and the reninangiotensin- aldosterone system in the regulation of blood pressure and the pathogenesis of essential hypertension. However, the genetic background of essential hypertension remains unclear. AIM: To determine the effects of genetic factors on selected indicators of the activity of the sympathoadrenal system and the renin-angiotensin-aldosterone system in twins. METHODS: We studied 39 monozygotic twin pairs (age 33+/-7 years) and 37 same-gender dizygotic twin pairs (age 36+/-7 years). We measured blood and urine adrenaline (A), noradrenaline (NA), dopamine (DA) and aldosterone (ALD) levels, as well as plasma renin activity (PRA) and serum angiotensin-converting enzyme (ACE) activity. Parameters of the genetic models for age- and gender-adjusted data were estimated by model fitting and path analysis technique using LISREL 8. RESULTS: The effects of genetic factors on the variability of blood and urine catecholamine levels were 69% and 65% for A, 42% and 76% for NA, and 58% and 40% for DA, respectively. We also found shared environmental components for blood NA (28%) and urine DA (17%). Genetic factors accounted for 36% of the variability of PRA and 80% of the variability of ACE. ALD levels were related only to environmental factors (including a shared environmental component, estimated at 25%, for urine ALD). CONCLUSIONS: We found significant effects of genetic factors on the activity of the sympathoadrenal system, as indicated by blood and urine catecholamine levels. We also found the effect of genetic factors on PRA and ACE, but not on aldosterone levels.
Subject(s)
Adrenal Glands/physiopathology , Blood Pressure/genetics , Hypertension/genetics , Renin-Angiotensin System/genetics , Sympathetic Nervous System/physiopathology , Adult , Aldosterone/blood , Aldosterone/urine , Dopamine/blood , Dopamine/urine , Epinephrine/blood , Epinephrine/urine , Female , Humans , Male , Norepinephrine/blood , Norepinephrine/urine , Peptidyl-Dipeptidase A/blood , Renin/blood , Twins, Dizygotic , Twins, MonozygoticABSTRACT
The most investigated novel risk factors of atherosclerosis are: fibrinogen (Fb), homocysteine (Hcy), lipoprotein (a) (Lp(a)), plasminogen activator inhibitor (PAI-1), markers of inflammation and infectious factors. Atherosclerotic renal artery stenosis (RAS) is a manifestation of generalized atherosclerosis and often coexist with hypertension and renal failure. The aim of the study was to assess plasma concentration of Hcy, von Willebrand factor (VWF), (Lp(a), Fb, PAI-1, and assessment of ACE gene polymorphism in pts with RAS and hypertension. The study included 15 patients with RAS (mean age 51.4 +/- 16.5 yrs) and 27 healthy volunteers (C) (mean age 42.9 +/- 9.5 yrs). Plasma concentrations of Hcy were significantly higher in RAS (11.0 +/- 3.9 mumol/L) than in C (6.8 +/- 1.3 mumol/L). Plasma concentration of VWF was also significantly higher in RAS than C (104.7 +/- 40 vs 73.6 +/- 20%) as was FB concentration (325.9 +/- 70.0 vs 256.2 +/- 54.7 mg%). DD genotype was present in 45% of RAS pts and in 12% of controls. In patients with atherosclerotic RAS novel markers of atherosclerosis may be an additional risk factor in the development and progression of atherosclerotic lesions.
Subject(s)
Arteriosclerosis/etiology , Arteriosclerosis/physiopathology , Hypertension, Renovascular/complications , Renal Artery Obstruction/complications , Renal Artery Obstruction/physiopathology , Adult , Arteriosclerosis/metabolism , Fibrinogen/metabolism , Homocysteine/metabolism , Humans , Lipoproteins/metabolism , Plasminogen Activator Inhibitor 1/metabolism , Risk FactorsABSTRACT
OBJECTIVE: Assessment of relationship between homocysteine (Hcy) and noradrenaline (NA), adrenaline (A) concentration and left ventricular mass index (LVMI) in patients with essential hypertension (EH). DESIGN AND METHODS: Samples obtained from 37 patients (14 female, 23 male) with mild EH (according to WHO criteria) (mean age 43.6 +/- 13.2 years) and 37 healthy volunteers (18 female, 19 male; mean age 38.2 +/- 10.6 years) were evaluated for Hcy (ELISA), NA and A (HPLC). Each patient underwent echocardiographic investigation with LVMI measurement (Penn convention). The examinations were performed in the outpatient clinic. RESULTS: Hcy was significantly higher in patients with EH (8.7 +/- 2.4 vs 6.6 +/- 1.3 micromol/l; p < 0.01). NA and A levels were significantly elevated in the EH group (A: 43.9 +/- 26.4 vs 36.9 +/- 29.4 pg/ml; NA: 428.5 +/- 148.8 pg/ml vs 314.6 +/- 103.4 pg/ml; both p < 0.05). LVMI was also significantly higher in EH group (96.6 +/- 19.5 vs 83.4 +/- 16.0 g/m2; p < 0.01). There was no significant correlation between Hcy and other analysed parameters in the studied groups. CONCLUSION: High levels of Hcy appear together with increased left ventricular mass and augmented adrenergic activity in patients with EH. Coexistence of high Hcy concentration, left ventricular hypertrophy and increased adrenergic activity increases the risk of atherosclerosis and cardiovascular disease in patients with EH.
Subject(s)
Epinephrine/blood , Homocysteine/blood , Hypertension/blood , Hypertrophy, Left Ventricular/blood , Norepinephrine/blood , Adult , Case-Control Studies , Chromatography, High Pressure Liquid , Echocardiography , Female , Humans , Hypertension/physiopathology , Male , Middle Aged , Regression AnalysisABSTRACT
The relationship between plasma leptin and catecholamine concentrations during chronic and acute catecholamine excess is studied. Patients with phaeochromocytoma, divided according to gender, were examined under basal conditions (n = 18) and at selected time-points during surgical removal of the tumour (n = 12). Appropriate controls were used (n = 23) for the basal study. Plasma leptin was determined by radioimmunoassay (RIA) and plasma noradrenaline (NA) and adrenaline (A) by high-performance liquid chromatography (HPLC). Statistical evaluation employed Student's t-test, Wicoxon test and Spearman's correlation coefficient. Gender-related differences in plasma leptin in normal subjects was confirmed, and these were maintained in the patients. Phaeochromocytoma patients had normal plasma leptin levels in the basal state and decreased levels following the massive catecholamine surge provoked by surgery. Plasma leptin concentration did not correlate with plasma NA or A in either group studied. In the patients with phaeochromocytoma, acute but not chronic catecholamine excess affected plasma leptin, suggesting a role for sympathetic activity in modulating leptin release.
Subject(s)
Adrenal Gland Neoplasms/blood , Epinephrine/blood , Leptin/blood , Norepinephrine/blood , Pheochromocytoma/blood , Adrenal Gland Neoplasms/surgery , Adult , Female , Humans , Male , Middle Aged , Neoplasm Proteins/blood , Pheochromocytoma/surgeryABSTRACT
The relationship between plasma leptin and catecholamine concentrations during chronic and acute catecholamine excess is studied. Patients with phaeochromocytoma, divided according to gender, were examined under basal conditions (n=18) and at selected time-points during surgical removal of the tumour (n=12). Appropriate controls were used (n=23) for the basal study. Plasma leptin was determined by radioimmunoassay (RIA) and plasma noradrenaline (NA) and adrenaline (A) by highperformance liquid chromatography (HPLC). Statistical evaluation employed Student's t-test, Wicoxon test and Spearman's correlation coefficient. Gender-related differences in plasma leptin in normal subjects was confirmed, and these were maintained in the patients. Phaeochromocytoma patients had normal plasma leptin levels in the basal state and decreased levels following the massive catecholamine surge provoked by surgery. Plasma leptin concentration did not correlate with plasma NA or A in either group studied. In the patients with phaeochromocytoma, acute but not chronic catecholamine excess affected plasma leptin, suggesting a role for sympathetic activity in modulating leptin release.