Angiotensin produced systemically or locally in tissues such as the brain plays an important role in the regulation of blood pressure and in the development of hypertension. We have established transgenic rats [TGR(ASrAOGEN)] expressing an antisense RNA against angiotensinogen mRNA specifically in the brain. In these animals, the brain angiotensinogen level is reduced by more than 90% and the drinking response to intracerebroventricular renin infusions is decreased markedly compared with control rats. Blood pressure of transgenic rats is lowered by 8 mmHg (1 mmHg ؍ 133 Pa) compared with control rats. Crossbreeding of TGR(ASrAOGEN) with a hypertensive transgenic rat strain exhibiting elevated angiotensin II levels in tissues results in a marked attenuation of the hypertensive phenotype. Moreover, TGR(ASrAOGEN) exhibit a diabetes insipidus-like syndrome producing an increased amount of urine with decreased osmolarity. The observed reduction in plasma vasopressin by 35% may mediate these phenotypes of TGR(ASrAOGEN). This new animal model presenting longterm and tissue-specific down-regulation of angiotensinogen corroborates the functional significance of local angiotensin production in the brain for the central regulation of blood pressure and for the pathogenesis of hypertension.Hypertension is a leading risk factor for cardiovascular diseases, and the molecular dissection of its complex genetic causes is a great challenge. As for most physiological processes, the brain also seems to play a dominant role in the regulation of blood pressure and the pathogenesis of hypertension (1). Already more than 50 years ago, centrally acting drugs have been introduced as effective therapeutics for this disease (2). One of the hormone systems crucially involved in the central control of blood pressure is the renin-angiotensin system (RAS) (1, 3). The genotype of angiotensinogen (AOGEN), the only precursor of the effector peptide angiotensin II, correlates with blood pressure in genetically engineered mice (4-6) and hypertensive patients (7,8). Mice with an AOGEN gene dose increased by transgenesis (4) or gene titration (5) exhibit enhanced blood pressure; animals with zero (6) or only one (5) AOGEN allele are hypotensive. In humans, certain AOGEN alleles are associated with higher plasma AOGEN levels and increased blood pressure (7,8).AOGEN not only is synthesized and secreted into the blood stream by the liver but also is produced locally in several organs, including the brain (9), representing the basis of tissue-based RAS. Because of the blood-brain barrier precluding circulating angiotensin II from accessing most of its central receptors, the brain RAS acts independently from the systemic RAS on blood pressure regulation by influencing the secretion of arginine-vasopressin (AVP) and adrenocorticotropic hormone and modulating the baroreceptor reflex and the sympathetic output (1, 9). However, despite high local production, the function and the significance of AOGEN and angiotensin II in the brain are only partially...
Classic characteristics are poor predictors of the risk of thromboembolism. Thus, better markers for the carotid atheroma plaque formation and symptom causing are needed. Our objective was to study by microarray analysis gene expression of genes involved in homeostasis of iron and heme in carotid atheroma plaque from the same patient. mRNA gene expression was measured by an Affymetrix GeneChip Human Gene 1.0 ST arrays (Affymetrix, Santa Clara, CA, USA) using RNA prepared from 68 specimens of endarteriectomy from 34 patients. Two genes involved in iron-heme homeostasis, CD163 and heme oxygenase (HO-1), were analysed in 34 plaques. CD163 (2.18, p01.45E-08) and HO-1 (fold-change 2.67, p02.07E-09) mRNAs were induced. We suggest that atheroma plaques show a more pronounced induction of CD163 and HO-1. Although further evidence is needed, our results support previous data. To our knowledge, this is the first report comparing gene expression between intact arterial tissue and carotid plaque using microarray analysis.
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