In dieser Arbeit wurden 8 und 16 Wochen alte, hypertensive "fawn-hooded" Ratten (FHH8, FHH16) mit genetisch ähnlichen 16 Wochen alten "fawn-hooded" Ratten mit nur geringgradiger Blutdruckerhöhung (FHL16, Kontrollgruppe) hinsichtlich der pathologisch-anatomischen Veränderungen der Nierenmorphologie und hinsichtlich der Expression von NO-Synthase-1 (NOS1), Cyclooxygenase-2 (COX-2) und Renin am juxtaglomerulären Apparat (JGA) verglichen. Die histopathologischen Veränderungen bei FHH16 umfassten die klassischen Schädigungszeichen der fokal segmentalen Glomerulosklerose (FSGS) mit fokaler Überexpression von Kollagen IV und eine moderate Arteriolopathie. Bei FHH8 ließen sich, wie bei FHL16 keine morphologischen Schädigungen nachweisen. Die NOS1-Aktivität an der Macula densa, untersucht mittels der NADPH-Diaphorasereaktion und die NOS1 mRNA Expression waren bei FHH8 (+153 and +88%; P < 0.05) und FHH16 (+93 and +98%; P < 0.05) im Vergleich zu FHL16 signifikant erhöht. Eine gleichgerichtete signifikante Erhöhung zeigte sich für die COX-2-Expression an der Macula densa von FHH8 (+166%; P < 0.05) und FHH16 (+157%; P < 0.05) im Vergleich zu FHL16. Des weiteren ließ sich eine signifikante, ebenfalls gleichgerichtete Überexpression von Renin in der afferenten Arteriole auf Protein- und mRNA-Ebene bei FHH8 (+51 and +166%; P < 0.05) und FHH16 (+105 and +136%; P < 0.05) im Vergleich zu FHL16 nachweisen. Somit konnte gezeigt werden, dass die gleichgerichtete Überexpression von NOS1, COX-2 und Renin am JGA bei der FHH-Ratte der Entwicklung einer fokal segmentalen Glomerulosklerose vorausgeht und damit möglicherweise pathogenetische Bedeutung für die Entstehung der Nierenschädigung bei diesem Rattenstamm hat. / This study describes elevated histochemical signals for nitric oxide synthase-1 (NOS1) and cyclooxygenase-2 (COX-2) in juxtaglomerular apparatus (JGA) and adjacent thick ascending limb of the kidney of fawn-hooded hypertensive rats (FHH). Two different age groups of FHH (8 and 16 wk; FHH8 and FHH16, respectively) were compared with genetically related fawn-hooded rats with close to normal blood pressure (FHL) that served as controls. Histopathological changes in FHH16 comprised focal segmental glomerulosclerosis (FSGS), focal matrix overexpression (mainly of collagen IV), and a moderate arteriolopathy with hypertrophy of the media, enhanced immunoreactivity for alpha-smooth muscle actin, and altered distribution of myofibrils. Macula densa NOS activity, as expressed by NADPH-diaphorase staining, and NOS1 mRNA abundance were significantly elevated in FHH8 (+153 and +88%; P < 0.05) and FHH16 (+93 and +98%; P < 0.05), respectively. Even higher elevations were registered for COX-2 immunoreactivity in FHH8 (+166%; P < 0.05) and FHH16 (+157%; P < 0.05). The intensity of renin immunoreactivity and renin mRNA expression in afferent arterioles was also elevated in FHH8 (+51 and +166%; P < 0.05) and FHH16 (+105 and +136%; P < 0.05), respectively. Thus we show that coordinate upregulation of tubular NOS1, COX-2, and renin expression precedes, and continues after, the manifestation of glomerulosclerotic damage in FHH. These observations may have implications in understanding the role of local paracrine mediators in glomerular disease.

Fetal pancreatic tissues can be a promising source for pancreatic progenitor cells (PPCs). In this regard, we have successfully isolated and characterized a population of fetal PPCs from first trimester human fetal pancreas using a previously established basic protocol. Upon exposure to a cocktail of conventional growth factors, these PPCs are amenable to differentiate into insulin-secreting islet-like cell clusters (ICCs); however, these ICCs have yet to exert additional efforts to direct to glucose-responsive cells. To address this issue, we have proposed two novel morphogenic factors in the present study, namely PDZ-domain-containing 2 (PDZD2) and angiotensin II (Ang II), a physiologically active peptide of the renin-angiotensin system (RAS), that potentially promote the differentiation and maturation of PPCs/ICCs. / In light of these findings, we conclude that we have discovered two novel mechanisms, the PDZD2 and Ang II/AT2 receptor signaling pathways, in the regulation of the development of PPCs/ICCs, thus implying their novel roles during islet development in vivo. The present study provides a "proof-of-principle" that a local RAS is critically involved in governing islet cell development. This work may contribute to devising protocols for maturation of pancreatic progenitors for clinical islet transplantation. / Local RASs have been reported to regulate the differentiation of tissue progenitor cells. It has yet to be confirmed whether such systems exist and govern the PPC development. To address this issue, we herein provided evidence that expression of RAS components was highly regulated throughout PPC differentiation. Locally generated Ang II was found to maintain PPC growth and differentiation via mediation of the Ang II type 1 and type 2 (AT1 and AT 2) receptors. We found that the AT2, but not AT1, receptor was a key mediator of Ang II-induced upregulation of beta-cell transcription factors. Transplantation of AT2 receptor-depleted ICCs into immune-privileged diabetic mice failed to ameliorate hyperglycemia, implying that AT2 receptors are indispensable during ICC maturation in vivo. / PDZD2 and its secreted form (sPDZD2) have been found to express in our fetal PPCs. We first evaluated the potential role of sPDZD2 in stimulating PPC differentiation and established an optimal concentration for such stimulation. We found that 10-9 M sPDZD2 promoted PPC differentiation, as evidenced by the up-regulation of the pancreatic endocrine markers and C-peptide content in the ICCs. It enhanced their expression of the L-type voltage-gated calcium ion channel (Cav1.2) and conferred an ability to secrete insulin in response to membrane depolarization. Yet these ICCs remained glucose-unresponsive because of the minimal expression of GLUT-2. We thus attempted to study another potential morphogenic candidate, Ang II. / To further test whether a functional RAS is present and if so, whether it regulates islet development in vivo, we employed a mouse embryo model at different embryonic days and reported a stronger AT2 receptor expression during the 2nd developmental transition of pancreas development. AT2 receptor blockade from e8.0 resulted in abnormalities in fetal pancreatic development. Neonates from these mother mice displayed destructed pancreas/islet architecture, a hampered ability in glucose-stimulated insulin-secretion possibly attributed to a decreased ratio of beta-cell to alpha-cell, and an impaired glucose tolerance at 4-wk old. / Leung, Kwan Keung. / Adviser: Po Sing Leung. / Source: Dissertation Abstracts International, Volume: 72-04, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 254-284). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Eine der häufigsten kardiovaskulären Erkrankungen ist die Atherosklerose. Bei der Entstehung einer Atherosklerose spielt eine Hyperlipoproteinämie eine entscheidende Rolle. Ein weiterer Faktor für die Entstehung kardiovaskulärer Erkrankungen ist ein hoher Blutdruck. In dieser Arbeit wurde eine mögliche Interaktion zwischen Lipoproteinen und den blutdruckregulierenden Endothelin- und Renin-Angiotensin-Systemen untersucht. Weiterführende Analysen erfolgten an Rezeptoren für die Aufnahme von nLDL und oxLDL. Abschließend wurden Signalwege untersucht, die durch nLDL und oxLDL aktiviert werden. Tierexperimentielle Untersuchungen in Aorten und Herzen fettreich gefütterter Wildtyp- Mäuse unterstützen die Zellkultur-Ergebnisse einer Induzierung des Endothelin-Systems durch erhöhte Lipoproteine. Zusammenfassend zeigt diese Arbeit neue Mechanismen der Interaktion von Lipoproteinen und blutdruckregulierenden Systemen in Endothelzellen. Die Rezeptoren scheinen dabei eine Schlüsselrolle zu spielen. Dies spricht für eine Potenzierung von Hyperlipoproteinämie und Hypertonie bei der Entstehung von Herz-Kreislauf-Erkrankungen.

The mechanisms whereby the pituitary gland maintains arterial pressure were investigated in rats. The arterial pressure in hypophysectomized rats was 30 mmHg below normal. Saralasin or captopril caused a further fall of 25 and 30 mmHg, respectively, suggesting that the renin-angiotensin system plays a role in blood pressure maintenance in hypophysectomized rats. Growth hormone administration to hypophysectomized rats increased the arterial pressure, but pretreatment with captopril prevented the effect. Plasma renin activity and basal renin secretion (in vitro) was normal in hypophysectomized rats despite a twofold greater renal renin content. Secretory responsiveness to isoproterenol and calcium omission was lower in hypophysectomized rats. It is concluded that the renin-angiotensin system plays a role in maintaining arterial blood pressure in hypophysectomized rats although the responsiveness of the system may be decreased.

O sistema renina-angiotensina (SRA) circulante é um sistema endócrino que promove a produção de angiotensina (Ang) II, a qual exerce seus efeitos pela interação com receptores específicos. O conceito clássico do SRA circulante está sendo modificado, pois tem sido demonstrada a existência de sistemas locais capazes de gerar angiotensinas de forma independente do SRA circulante em vários tecidos e órgãos. Trabalhos recentes sugerem a existência de alguns componentes do SRA em tecido gengival e fibroblastos gengivais de diferentes espécies. Porém, não são encontrados na literatura achados inequívocos sobre a presença de importantes componentes do SRA, tais como renina e angiotensinogênio, no tecido gengival de rato. Portanto, os objetivos do presente trabalho foram: 1) estudar a expressão e localização de componentes do SRA no tecido gengival de rato e 2) estudar in vitro a funcionalidade do SRA local em homogenato de tecido gengival de rato quanto à formação de Ang II e outros peptídeos vasoativos a partir de precursores de Ang II. Transcrição reversa seguida de reação em cadeia da polimerase (RTPCR) foi utilizada para avaliar a expressão de RNAm. Análise imunohistoquímica foi utilizada para detecção e localização de renina no tecido gengival de rato. Um método fluorimétrico padronizado com o tripeptídeo Hipuril-Histidina-Leucina (Hip-His-Leu) foi usado para medir a atividade da ECA em homogenatos de tecido gengival de rato. A técnica de cromatografia líqüida de alto desempenho (HPLC) foi usada para analisar os produtos formados após a incubação de homogenatos de tecido gengival de rato com Ang I ou tetradecapeptídeo substrato de renina (TDP). RT-PCR revelou a expressão de RNAm para renina, angiotensinogênio, ECA e receptores de Ang II (AT1a, AT1b e AT2) em tecido gengival; em fibroblastos cultivados de tecido gengival foi observada expressão de RNAm para renina, angiotensinogênio e receptor AT1a. A técnica de imunohistoquímica demonstrou a existência de renina em vasos de tecido gengival de rato. Atividade da ECA foi detectada por meio do ensaio fluorimétrico (4,95±0,89 nmol His-Leu/g.min). Quando Ang I foi usada como substrato, análises de HPLC mostraram a formação de Ang 1-9 (0,576±0,128 nmol/mg.min), Ang II (0,066±0,008 nmol/mg.min) e Ang 1-7 (0,111±0,017 nmol/mg.min), enquanto que os mesmos peptídeos (0,139±0,031; 0,206±0,046 e 0,039±0,007 nmol/mg.min, respectivamente) e Ang I (0,973±0,139 nmol/mg.min) foram formados quando TDP foi usado como substrato. Adicionalmente, análises de HPLC revelaram a ausência de enzimas que degradam Ang II em homogenatos de tecido gengival de rato. Em conclusão, os resultados apresentados neste trabalho mostram claramente a existência de um SRA local em tecido gengival de rato, que é capaz de gerar Ang II e outros peptídeos vasoativos in vitro. Estudos adicionais são necessários para elucidar o papel deste sistema local no tecido gengival de rato. / Systemic renin-angiotensin system (RAS) promotes the plasmatic production of angiotensin (Ang) II, which acts through the interaction with specific receptors. The concept of this classic circulating RAS has been modified since there is growing evidence that local systems in various tissues and organs are capable of generating angiotensins independently of the circulating RAS. Recent works suggest the existence of some RAS components in the gingival tissue and cultured gingival fibroblasts of different species, but there is paucity of data in the literature regarding the unequivocal existence of crucial RAS components, such as renin and angiotensinogen, in the rat gingival tissue. Therefore, the aims of the present work were to: 1) study the expression and localization of RAS components in the rat gingival tissue and 2) evaluate the in vitro production of Ang II and other peptides catalyzed by rat gingival tissue homogenates incubated with different precursors of Ang II. Reverse transcription-polymerase chain reaction (RT-PCR) was used to assess mRNA expression. Immunohistochemical (IHC) analysis aimed to detect and localize renin in the rat gingival tissue. A standardized fluorimetric method with the tripeptide Hippuryl-Histidyl-Leucine (Hip-His-Leu) was used to measure tissue ACE activity in rat gingival tissue homogenates. High performance liquid chromatography (HLPC) was used to analyze the products formed after the incubation of rat gingival tissue homogenates with Ang I or tetradecapeptide renin substrate (TDP). RT-PCR revealed the mRNA expression for renin, angiotensinogen, ACE and Ang II receptors (AT1a, AT1b and AT2) in the rat gingival tissue; cultured gingival fibroblasts expressed renin, angiotensinogen and AT1a receptor. IHC demonstrated the existence of renin in vessels of the rat gingival tissue. ACE activity was detected by the fluorimetric assay (4.95±0.89 nmol His-Leu/g.min). When Ang I was used as the substrate, HPLC analyses showed the formation of Ang 1-9 (0.576±0.128 nmol/mg.min), Ang II (0.066±0.008 nmol/mg.min) and Ang 1-7 (0.111±0.017 nmol/mg.min) whereas these same peptides (0.139±0.031; 0.206±0.046 and 0.039±0.007 nmol/mg.min, respectively) and Ang I (0.973±0.139 nmol/mg.min) were formed when TDP was the substrate. Additionally, HPLC revealed absence of Ang II degrading enzymes in rat gingival tissue homogenates. In conclusion, the results presented here clearly show the existence of a local RAS in the rat gingival tissue, which is capable of generating Ang II and other vasoactive peptides in vitro. Further studies are required to elucidate the role of this system in the rat gingival tissue.

Hypertonie ist die häufigste adipositas-assoziierte Erkrankung. Das vermehrt vorhandene Fettgewebe könnte von pathophysiologischer Bedeutung sein, da es eine Reihe von Substanzen sezerniert, die die Blutdruckregulation beeinflussen. Hinweise auf eine Rolle des adipocytären Renin-Angiotensin Systems für die Hypertonie ergeben sich aus der Assoziation von Adipositas und einer gesteigerten systemischen Aktivität des Renin-Angiotensin Systems, sowie aus dem Nachweis im Tiermodell, dass adipocytär gebildetes Angiotensinogen in die systemische Zirkulation gelangt. In der vorliegenden Untersuchung wurden 12 schlanke Normotonikerinnen, 8 adipöse Normotonikerinnen und 10 adipöse Hypertonikerinnen charakterisiert und die adipocytäre Genexpression des Renin-Angiotensin Systems untersucht. Adipocyten wurden mittels Nadelbiopsie und Kollagenaseverdau gewonnen, die Genexpression wurde durch real-time RT-PCR bestimmt. Der Vergleich der drei Gruppen zeigt, dass Adipositas mit einer Reduktion der Angiotensinogen-Expression einhergeht, die adipositas-assoziierte Hypertonie mit einer gesteigerten Expression von Renin, Angiotensin-Converting-Enzyme und Angiotensin II-Typ 1-Rezeptor. Dies führt zu der Hypothese, dass im Fettgewebe adipöser Hypertoniker vermehrt Angiotensin II gebildet wird und könnte den positiven Einfluß von ACE-Hemmern auf die Insulinresistenz und die Verringerung der Neuerkrankungsrate an Diabetes mellitus Typ 2 erklären. / Adipose tissue secretes vasoactive substances which may contribute to the development of obesity-related hypertension. We aimed to study the differential expression of renin-angiotensin system genes in subcutaneous abdominal adipocytes of 12 lean normotensive, 8 obese normotensive, and 10 obese hypertensive women in a cross-sectional study. 24h ambulatory blood pressure measurement, clinical chemistry, and anthropometry were used to characterize the volunteers. Adipocytes were obtained by abdominal subcutaneous needle biopsy and collagenase digestion. Gene expression was studied by quantitative real time RT-PCR. While expression of the angiotensinogen gene was significantly lower in adipocytes from both obese groups, the renin, angiotensin-converting enzyme and angiotensin II-type 1-receptor genes were significantly upregulated in obese hypertensives. In conclusion, renin-angiotensin system genes are differentially regulated in human obesity and hypertension. The data obtained suggest increased formation of angiotensin II in adipose tissue of obese hypertensive subjects. The role of the adipose-tissue renin-angiotensin system in the development of obesity-associated hypertension or metabolic disease clearly warrants further study.

Das Renin-Angiotensin-System ist nachweislich in die Entwicklung der schwangerschaftsspezifischen Erkrankung Präeklampsie involviert. Ziel der Arbeit ist die Charakterisierung der Effekte des zirkulierenden sowie uteroplazentaren Renin-Angiotensin-Systems im Rattenmodell. Wurden weibliche Ratten, transgen für humanes Angiotensinogen, mit männlichen Ratten, transgen für humanes Renin verpaart, so entwickelten sie während der Schwangerschaft Bluthochdruck und Proteinurie, während die umgekehrte Kreuzung diese Hauptsymptome der Präeklampsie nicht zeigte. Weiterhin wurde mit einer Kontrollgruppe sowie einer Angiotensin II behandelten Gruppe gearbeitet. Chronisch, systemische Angiotensin II Infusion (1000 ng/kg/min) erhöhte zirkulierendes Angiotensin II während in der umgekehrten, Präeklampsie-negativen Kreuzung uteroplazentares Angiotensin II erhöht war. In der Präeklampsie-positiven Gruppe war Angiotensin II zirkulär und uteroplazentar erhöht. Bluthochdruck und Albuminurie waren alleinig in den Tiermodellen mit erhöhtem zirkulierendem Angiotensin II nachweisbar. In der Kontrollgruppe kam es während der Schwangerschaft zu einer physiologischen Herzhypertrophie, während in der Präeklampsie-positiven Gruppe Anzeichen einer pathologischen Herzhypertrophie nachweisbar waren. Weiterhin unterstützte uteroplazentares Angiotensin II die tiefe Invasion von Trophoblasten in plazentafernen Spiralarterien, während zirkulierendes Angiotensin II die Trophoblasteninvasion im gesamten mesometrialen Dreieck diffus förderte. In Zellkulturexperimenten konnte gezeigt werden, dass Angiotensin II die Mobilität und die Invasion einer Trophoblastenzelllinie förderte. Ebenso erhöhte Angiotensin II die Migration von Trophoblasten in Plazentakulturen. Diese Ergebnisse verdeutlichen den unterschiedlichen Einfluss des zirkulierenden und uteroplazentaren Renin-Angiotensin-Systems auf die Schwangerschaft und tragen damit zum Verständnis pathologischer Prozesse bei, die zu Präeklampsie führen. / Dysregulation of the renin-angiotensin-system is important in preeclampsia, a pregnancy specific disorder, characterized by high blood pressure and albuminuria. Aim of this study is to characterize the effects of circulation and uteroplacental renin-angiotensin-system during pregnancy in a rat model. Female rats transgenic for the human angiotensinogen gene crossed with males transgenic for the human renin gene develop preeclampsia, whereas those of the opposite cross do not. We used this model to study the role of angiotensin II in trophoblast invasion, which is shallow in human preeclampsia but deeper in this model. We investigated the following groups: preeclampsia rats, opposite-cross rats, angiotensin II–infused rats and control rats. Angiotensin II infusion increased only circulating angiotensin II levels, opposite cross influenced only uteroplacental angiotensin II and preeclampsia rats showed increased circulating and uteroplacental angiotensin II. Blood pressure and albuminuria occurred in the models with high circulating angiotensin II but not in other models. Control rats showed physiological heart hypertrophy during pregnancy whereas pathological heart hypertrophy occurred in preeclampsia rats. High uteroplacental angiotensin II influenced deep trophoblast invasion in distant spiral arteries whilst the effect of circulating angiotensin II was more diffuse. We then studied human trophoblast cell line and villous explants derived from first-trimester pregnancy. Local angiotensin II dose-dependently increased migration, invasion and motility. The data suggest that angiotensin II stimulates trophoblast invasion in vivo in the rat and in vitro in human cells, a hitherto fore unrecognized function.

Jiang, Lili. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 215-235). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

研究背景和目的 / 高血壓和糖尿病是人群中常見的疾病，兩者常共同存在，其共存的病理生理機制非常複雜，其中腎素血管景張素系統功能紊亂起重要作用。多個研究表明血管緊張素轉化晦抑制劑和血管緊張素II 1 型受體阻滯劑通過調節不同基因的表達，發揮其保護心血管和腎臟功能的效用。然而，目前仍缺乏遠兩類藥物影響全基因表達譜的全面調查。因此，本研究應用全基因表達譜晶片技術，檢測分析了高血壓和糖尿病並發的病人在服用安慰劑、雷米普利(ramipril)和替米沙坦(telmisartan)後的全基因表達譜的變化，從而全面評估了血管緊張素轉化臨抑制劑和血管繁張素II 1 型受體阻滯劑對相關基因的轉錄調控作用。 / 方法 / 11 名患有高血壓和糖尿病的病人(男性5 名)在服用安慰劑最少2 星期后，以隨機吹序接受為期各6 星期的雷米普利和替米沙坦治療，並分別在安慰劑期和2 個藥物治療期結束后提取心A 進行全基因表達譜分析。 / 結果 / 與服用安慰劑時的全基因表達譜相比，雷米普利治療后有267 個基因的表達降低， 99 個基因的表達增強。表達差異幅度為-2.0 至1.3 (P < 0.05) 。表達下降的基因主要與血管平滑肌收縮、炎症反應和氧化壓力相關。表達增強的基因主要與心血管炎症反應負調節相關。基因共表達網絡分析表明， 2 個共表達基因組與雷米普利的降血壓作用相闕， 3 個共表達基因組與肥胖相關。 / 與服用安慰劑時的全基因表達譜相比， 替米拉)、坦治療后有55 個基因表達降低， 158 個基因的表達增強。表達差異幅度為-1. 9 至1.3 (P < 0.05) 。表達增強的基因主要與脂質代謝、糖代謝和抗炎症因子作用相關。基因共表達網絡分析表明， 2 個共表達基因組與替米沙坦對24 小時舒張壓負荷量的作用相關， 2 個共表達基因組則與總膽固醇， 低密度脂蛋白膽固醇和C 反應蛋白相關。 / 結論 / 本論文描述了高血壓和2 型糖尿病病患全基因組表達的總體模式及經藥物治療後表達譜的相應改變， 為今後進一步研究腎素血管緊張素系統抑制劑和高血壓、糖尿病發展進程的相互作用提供了方向。 / Background and aim: Pathophysiological mechanisms underpinning the coexistence of hypertension and type 2 diabetes are complex systemic responses involving dysregulation of the renin-angiotensin system (RAS). We conducted this study to investigate the genome wide gene expression changes in patients with both hypertension and diabetes at three treatment stages, including placebo, ramipril and telmisartan. This study aimed to obtain a panoramic view of interactions between gene transcription and antihypertensive therapy by RAS inhibition. / Methods: 11 diabetic patients (S men) with hypertension were treated with placebo for at least 2 weeks followed by 6 weeks randomised crossover treatment with ramipril Smg daily and telmisartan 40mg daily, respectively. Total RNA were extracted from leukocytes at the end of placebo and each treatment period, and were hybridized to the whole transcript microarray. The limma package for R was used to identify differentially expressed genes between placebo and the 2 active treatments. The weighted gene coexpression network analysis (WGCNA) was applied to identify groups of genes (modules) highly correlated to a common biological function in pathogenesis and progression of hypertension and diabetes. / Results: There were 267 genes down-regulated and 99 genes up-regulated with ramipril. Fold changes of gene expression were ranged from -2.0 to 1.3 (P < 0.05). The down-regulated genes were involved in vascular signalling pathways responsible for vascular smooth muscle contraction, inflammation and oxidative stress. The up-regulated genes were associated with negative regulation of cardiovascular inflammation. The WGCNA identified 17 coexpression gene modules related to ramipril. The midnight blue (57 genes, r < -0.44, P < 0.05) and magenta (190 genes, r < -0.44, P < 0.05) modules were significantly correlated to blood pressure differences between placebo and ramipril. / There were 55 genes down-regulated and 158 genes up-regulated with telmisartan. Fold changes of gene expression were ranged from -1.9 to 1.3 (P < 0.05). The down-regulated genes were mainly associated with cardiovascular inflammation and oxidative stress. The up-regulated genes were associated with lipid and glucose metabolism and anti-inflammatory actions. The WGCNA identified 8 coexpression gene modules related to telmisartan. The black (56 genes, r = 0.46, P = 0.03) and turquoise (1340 genes, r = -0.48, P = 0.02) modules were correlated with diastolic blood pressure load. The blue (1027 genes) module was enriched with genes correlated with total cholesterol (r = - 0.52, P = 0.01), LDL-C (r = - 0.58, P = 0.004), and hsCRP (r = -0.57, P = 0.006). The green module (272 genes) was significantly correlated with LDL-C (r = - 0.44, P = 0.04) and hsCRP (r = - 0.59, P = 0.004). / Conclusion: Genome wide gene expression profiling in this study describes the general pattern and treatment responses in patients with hypertension and type 2 diabetes, which suggests future directions for further investigations on the interaction between actions of the RAS blockers and disease progression. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Deng, Hanbing. / "December 2011." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 198-256). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese. / Declaration --- p.i / Publications --- p.ii / Abstract --- p.iv / 論文摘要 --- p.vi / Acknowledgements --- p.viii / Table of Contents --- p.x / List of tables --- p.xiv / List of figures --- p.xv / List of appendices --- p.xvii / List of abbreviations --- p.xviii / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Overview --- p.1 / Chapter 1.2 --- Epidemiology --- p.6 / Chapter 1.2.1 --- Epidemiology of hypertension --- p.9 / Chapter 1.2.2 --- Epidemiology of type 2 diabetes --- p.10 / Chapter 1.3 --- Aetiology --- p.13 / Chapter 1.3.1 --- Ageing --- p.13 / Chapter 1.3.1.1 --- Age-induced artery stiffness --- p.14 / Chapter 1.3.1.2 --- Age-related endothelial dysfunction --- p.14 / Chapter 1.3.2 --- The renin-angiotensin system (RAS) --- p.16 / Chapter 1.3.2.1 --- The local RAS --- p.20 / Chapter 1.3.2.2 --- The RAS and insulin resistance --- p.22 / Chapter 1.3.2.3 --- The RAS and inflammation --- p.26 / Chapter 1.3.2.4 --- The RAS and oxidative stress --- p.28 / Chapter 1.3.3 --- Obesity --- p.31 / Chapter 1.3.3.1 --- Obesity and renin-angiotensin system (RAS) --- p.33 / Chapter 1.3.3.2 --- Obesity and insulin resistance --- p.36 / Chapter 1.3.3.3 --- Obesity and oxidative stress --- p.38 / Chapter 1.3.3.4 --- Obesity and sympathetic nervous system (SNS) --- p.38 / Chapter 1.4 --- Pharmacogenomics of antihypertensive therapy --- p.39 / Chapter 1.4.1 --- Angiotensin-converting enzyme inhibitors (ACEIs) --- p.41 / Chapter 1.4.2 --- Angiotensin II type 1 receptor blockers (ARBs) --- p.43 / Chapter Chapter 2 --- Aim --- p.59 / Chapter Chapter 3 --- Methods --- p.60 / Chapter 3.1 --- Subjects --- p.60 / Chapter 3.1.1 --- Subject recruitment protocol --- p.60 / Chapter 3.1.2 --- Definition of type 2 diabetes --- p.62 / Chapter 3.1.3 --- Definition of obesity --- p.62 / Chapter 3.1.4 --- Definition of dyslipidaemia --- p.63 / Chapter 3.2 --- Study design and procedure --- p.64 / Chapter 3.2.1 --- Blood pressure assessments --- p.65 / Chapter 3.2.2 --- Anthropometric measurements --- p.68 / Chapter 3.2.3 --- Medical history, life style and side effect evaluation --- p.68 / Chapter 3.2.4 --- RNA isolation --- p.68 / Chapter 3.2.5 --- RNA quality assessment --- p.70 / Chapter 3.2.6 --- Oligonucleotide microarrays --- p.71 / Chapter 3.2.7 --- DNA extraction --- p.75 / Chapter 3.2.8 --- Biomedical measurements --- p.76 / Chapter 3.2.8.1 --- Glycosylated haemoglobin Alc (HbA₁c) --- p.77 / Chapter 3.2.8.2 --- Fasting plasma glucose (FP G) --- p.77 / Chapter 3.2.8.3 --- Fasting insulin --- p.77 / Chapter 3.2.8.4 --- Plasma urate --- p.77 / Chapter 3.2.8.5 --- High sensitive C-reactive protein (hsCRP) --- p.78 / Chapter 3.2.8.6 --- Fasting plasma triglycerides (TG) --- p.78 / Chapter 3.2.8.7 --- Fasting plasma cholesterols --- p.78 / Chapter 3.2.8.8 --- Renal and liver functions --- p.78 / Chapter 3.2.8.9 --- Urinary parameters --- p.79 / Chapter 3.3 --- Statistical Analysis --- p.79 / Chapter 3.3.1 --- Statistical analysis of clinical and biomedical data --- p.79 / Chapter 3.3.2 --- Analysis of microarray data --- p.80 / Chapter 3.3.2.1 --- Raw data assessment --- p.80 / Chapter 3.3.2.2 --- Data normalisation --- p.92 / Chapter 3.3.2.3 --- Data filtering --- p.96 / Chapter 3.3.2.4 --- Linear models for assessment of differential expression --- p.96 / Chapter 3.3.2.5 --- Weighted gene coexpression network analysis --- p.101 / Chapter 3.3.2.6 --- Network visualisation and gene ontology analysis --- p.102 / Chapter 3.3.3 --- Sample size calculation --- p.103 / Chapter Chapter 4 --- Results --- p.104 / Chapter 4.1 --- Demographic and biomedical characteristics at baseline --- p.104 / Chapter 4.1.1 --- Hypertension and diabetes status at baseline --- p.108 / Chapter 4.1.2 --- Prevalence of dyslipidaemia --- p.108 / Chapter 4.1.3 --- Prevalence of obesity --- p.109 / Chapter 4.1.4 --- Prevalence of metabolic syndrome --- p.109 / Chapter 4.1.5 --- Inflammation markers --- p.110 / Chapter 4.2 --- Blood pressure response to the RAS blockers --- p.110 / Chapter 4.2.1 --- Clinic blood pressure --- p.110 / Chapter 4.2.2 --- 24-hour ambulatory blood pressure --- p.112 / Chapter 4.3 --- Biomedical characteristics --- p.118 / Chapter 4.4 --- Compliance, side effects and adverse events --- p.120 / Chapter 4.5 --- Gene expression differences between treatments --- p.121 / Chapter 4.5.1 --- Gene expression differences between placebo and ramipril --- p.121 / Chapter 4.5.1.1 --- Expression changes in genes related to regulation of transcription with ramipril --- p.122 / Chapter 4.5.1.2 --- Expression changes with ramipril in genes related to molecular mechanism of cardiovascular changes in hypertension --- p.125 / Chapter 4.5.1.3 --- Expression changes in genes related to blood pressure with ramipril --- p.128 / Chapter 4.5.1.4 --- Expression changes in genes related to fatty acid metabolism with ramipril --- p.130 / Chapter 4.5.1.5 --- Expression changes in genes related to inflammation with ramipril --- p.130 / Chapter 4.5.1.6 --- Expression changes in genes related to oxidative stress with ramipril --- p.133 / Chapter 4.5.1.7 --- Power estimation --- p.133 / Chapter 4.5.2 --- Gene expression differences between placebo and telmisartan --- p.135 / Chapter 4.5.2.1 --- Changes in regulation oftranscription with telmisartan --- p.137 / Chapter 4.5.2.2 --- Expression changes in genes related to glucose metabolism with telmisartan --- p.141 / Chapter 4.5.2.3 --- Expression changes in genes related to lipid metabolism with telmisartan --- p.143 / Chapter 4.5.2.4 --- Expression changes in genes related to inflammation with telmisartan --- p.143 / Chapter 4.5.2.5 --- Power estimation --- p.145 / Chapter 4.5.3 --- WGCNA for comparison between placebo and ramipriI --- p.147 / Chapter 4.5.3.1 --- Midnight blue module and clinical responses to ramipril --- p.152 / Chapter 4.5.3.2 --- Magenta module and blood pressure responses to ramipril --- p.154 / Chapter 4.5.3.3 --- Yellow module and clinical responses to ramipril --- p.158 / Chapter 4.5.3.4 --- Red module and clinical responses to ramipril --- p.161 / Chapter 4.5.3.5 --- Salmon module and clinical responses to ramipril --- p.163 / Chapter 4.5.4 --- WGCNA for comparison between placebo and telmisaItan --- p.168 / Chapter 4.5.4.1 --- Diastolic blood pressure load and gene coexpression modules --- p.168 / Chapter 4.5.4.2 --- Lipids, hsCRP and gene coexpression modules --- p.172 / Chapter Chapter 5 --- Discussion --- p.176 / Chapter 5.1 --- Gene expression changes related to ramipril --- p.177 / Chapter 5.1.1 --- Gene expression changes and blood pressure reduction by ramipri1 --- p.177 / Chapter 5.1.2 --- Gene expression changes and vascular protection by ramipri1 --- p.181 / Chapter 5.1.3 --- Obesity and gene expression changes by ramipril --- p.183 / Chapter 5.2 --- Gene expression changes related to telmisartan --- p.185 / Chapter 5.2.1 --- Blood pressure and coexpressed gene modules with telmisartan --- p.185 / Chapter 5.2.2 --- Lipid metabolism and gene expression changes by telmisartan --- p.187 / Chapter 5.2.3 --- Glucose metabolism and gene expression changes by telmisartan --- p.189 / Chapter 5.2.4 --- hsCRP and gene expression changes by telmisartan --- p.190 / Chapter 5.3 --- Limitations of this study and future directions of research --- p.191 / Chapter Chapter 6 --- Conclusion --- p.194 / References --- p.198 / Appendices --- p.257

Chronic treatment with enalapril and valsartan significantly improved endothelium-dependent relaxations of aortas from ovariectomized rats. The present results clearly point to that chronic treatment with enalapril or valsartan reduced expression and function of RAS and associated oxidative stress, thereby augmented NO bioavailability and improved endothelium-dependent relaxations. These results provided novel evidence supporting a potential application of ACEI and ARB in the treatment of endothelial dysfunction-associated vascular complications in postmenopausal women. / Functional studies showed that acetylcholine-induced relaxations in isolated aortas were impaired in a time-dependent manner, from the 4th-week to the 12th-week after ovariectomy. The impaired relaxations were partially restored by acute treatment with losartan [angiotensin II type 1 receptor (AT1R) blocker] and apocynin [NAD(P)H oxidase inhibitor]. The present results demonstrate that estrogen deficiency blunted endothelium-dependent relaxations due to impaired the NO bioavailability, which is closely associated with the reduced eNOS activity and elevated RAS expression and associated NAD(P)H oxidase-mediated oxidative stress in the vascular wall. / The present study shows that chronic consumption of cranberry juice restored the endothelium-dependent relaxations in aortas from ovariectomized rats. In ovariectomized rats, the phenylephrine-induced a higher active vascular tension; which was prevented by chronic consumption of cranberry juice. The present data also shows that cranberry juice administration significantly reduces the elevated serum levels of total cholesterol, triglyceride, high density lipoprotein (HDL) cholesterol, non-HDL (nHDL) cholesterol, and nHDL/HDL. The active ingredients in the cranberry juice organic extract accounting for the vascular benefit remain to be further examined even though the extract causes endothelial NO-dependent relaxations in normal rat aortas and contains several bioactive compounds, some of which may protect the vascular function. This study provides the first line of evidence concerning a significant vascular benefit of chronic consumption of cranberry juice during estrogen deficiency. (Abstract shortened by UMI.) / The present study used ovariectomized female rats that mimic the "equivalent" state of menopause in human and investigated whether dysregulation of RAS components contribute to endothelial dysfunction and whether chronic treatment with ACEI (enalapril) or ARB (valsartan) could restore endothelial function in ovariectomized rats. / The second objective of the present study was to investigate whether or not consumption of cranberry juice, a popular drink in Western countries, could restore endothelial function during estrogen deficiency and to elucidate the cellular mechanisms underlying the improved endothelial function. / Yung, Lai Ming. / Adviser: Huana Yu. / Source: Dissertation Abstracts International, Volume: 70-06, Section: B, page: 3252. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2008. / Includes bibliographical references (leaves 148-168). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.