Thesis--Wisconsin. / Vita. Includes bibliographical references (leaves 110-112).

Thesis (M.S.)--University of Missouri-Columbia, 2008. / "May 2008" The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Includes bibliographical references.

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The role of the Angiopoietin-1 (Ang1)-Tie2 pathway in pulmonary arterial hypertension (PAH) is controversial, with one group suggesting that increased Ang1-Tie2 activity may even play a causal role in PAH progression. However, Ang1 has been well-characterized as a homeostatic factor, which prevents endothelial cell (EC) activation and injury through Tie2 receptor stimulation. Furthermore, we have previously demonstrated that lung Tie2 expression and activity are significantly downregulated in experimental PAH, implicating reduced Tie2 signaling in the pathogenesis of this disease. Thus, we hypothesized that manipulations to increase Ang1-Tie2 signaling will protect against lung EC injury and onset of PAH, whereas a loss-of-function of this pathway in Tie2-deficient mice (Tie2+/-) would predispose to PAH. Approximately 13% of Tie2+/- mice developed spontaneous elevation in right ventricular systolic pressure (RVSP), although no significant difference was observed between the WT and Tie2+/- groups following chronic hypoxic exposure. Serotonin (5-HT) infusion for one week or daily interleukin-6 (IL-6) injection for two weeks produced substantial RVSP elevations in Tie2+/-, but not WT mice (P<0.05). Following one week of 5-HT or IL-6 treatment, there was a significant decrease in Ang1 protein expression in both WT and Tie2+/- mice (P<0.05). Similarly, following exposure of cultured pulmonary arterial smooth muscle cells to 5-HT or IL-6, Ang1 secretion was significantly decreased (P<0.01). Moreover, 5-HT or IL-6 exposure resulted in decreased Tie2 activity and increased apoptosis only in the lungs of Tie2+/- mice (P<0.01), and treatment with a pan-caspase inhibitor, Z-VAD, prevented PAH in 5-HT-treated Tie2-deficient mice. Together with in vitro studies showing that pulmonary arterial ECs subjected to Tie2-siRNA were more susceptible to apoptosis following 5-HT treatment, this strongly implicates EC death as a primary mechanism of PAH in the presence of reduced Tie2 activity. In addition, doxycycline-conditional, endothelial-targeted Ang1 binary transgenic mice showed no evidence of elevated RVSP under basal conditions and if anything, demonstrated a blunted response to 5-HT treatment compared to non-binary littermate controls. Therefore, our findings support the importance of EC survival-signaling via the Ang1-Tie2 pathway as a protective mechanism in PAH and emphasize the pivotal role of EC apoptosis in the onset of this disease.

The role of the Angiopoietin-1 (Ang1)-Tie2 pathway in pulmonary arterial hypertension (PAH) is controversial, with one group suggesting that increased Ang1-Tie2 activity may even play a causal role in PAH progression. However, Ang1 has been well-characterized as a homeostatic factor, which prevents endothelial cell (EC) activation and injury through Tie2 receptor stimulation. Furthermore, we have previously demonstrated that lung Tie2 expression and activity are significantly downregulated in experimental PAH, implicating reduced Tie2 signaling in the pathogenesis of this disease. Thus, we hypothesized that manipulations to increase Ang1-Tie2 signaling will protect against lung EC injury and onset of PAH, whereas a loss-of-function of this pathway in Tie2-deficient mice (Tie2+/-) would predispose to PAH. Approximately 13% of Tie2+/- mice developed spontaneous elevation in right ventricular systolic pressure (RVSP), although no significant difference was observed between the WT and Tie2+/- groups following chronic hypoxic exposure. Serotonin (5-HT) infusion for one week or daily interleukin-6 (IL-6) injection for two weeks produced substantial RVSP elevations in Tie2+/-, but not WT mice (P<0.05). Following one week of 5-HT or IL-6 treatment, there was a significant decrease in Ang1 protein expression in both WT and Tie2+/- mice (P<0.05). Similarly, following exposure of cultured pulmonary arterial smooth muscle cells to 5-HT or IL-6, Ang1 secretion was significantly decreased (P<0.01). Moreover, 5-HT or IL-6 exposure resulted in decreased Tie2 activity and increased apoptosis only in the lungs of Tie2+/- mice (P<0.01), and treatment with a pan-caspase inhibitor, Z-VAD, prevented PAH in 5-HT-treated Tie2-deficient mice. Together with in vitro studies showing that pulmonary arterial ECs subjected to Tie2-siRNA were more susceptible to apoptosis following 5-HT treatment, this strongly implicates EC death as a primary mechanism of PAH in the presence of reduced Tie2 activity. In addition, doxycycline-conditional, endothelial-targeted Ang1 binary transgenic mice showed no evidence of elevated RVSP under basal conditions and if anything, demonstrated a blunted response to 5-HT treatment compared to non-binary littermate controls. Therefore, our findings support the importance of EC survival-signaling via the Ang1-Tie2 pathway as a protective mechanism in PAH and emphasize the pivotal role of EC apoptosis in the onset of this disease.

Thesis (Ph.D.) - University of Glasgow, 2007. / Ph.D. thesis submitted to the Division of Neuroscience and Biomedical Systems, Institute of Biomedical and Life Sciences, University of Glasgow, 2007. Includes bibliographical references. Print version also available.

The diagnosis of primary pulmonary hypertension (PPH) and prediction of its course, whether treated or untreated, presents several problems. These are of particular relevance when selection of patients for, and timing of heart-lung transplantation is being considered. I performed a retrospective study on patients with PPH and chronic large vessel thromboembolic pulmonary hypertension (TPH) seen at Groote Schuur Hospital between 1957 and 1985 in an attempt to: 1. Establish the diagnostic and prognostic value of clinical features, lung function tests, cardiac catheterisation, isotope lung scans and, in the PPH group, response to therapy; 2. Review our experience of the effects of treatment with vasodilators and oral anticoagulants, and the results of heart and lung transplantation in the PPH group; 3. Attempt to identify features which could be used to predict prognosis in PPH; and thereby 4. Define criteria for selecting PPH patients whose prognosis could be improved by heart-lung transplantation.

Includes bibliographical references / Pulmonary hypertension (PH) is defined as a rise in the pressure in the pulmonary arteries resulting from a variety of diseases including chronic infectious diseases, lung diseases and left heart diseases (LHD). It is a global health problem and accounts for a substantial portion of cardiovascular disease. PH due to LHD (PH-LHD) is credited to be the most common form of PH worldwide and is associated with adverse outcomes. Considering the suggestions of high prevalence and potential adverse outcomes of PH in sub-Saharan Africa (SSA), the investigation of the etiologies, clinical profile, correlates, and outcomes of PH-LHD in this region is a medical priority. Methods: Through a systematic review, we assessed existing evidence on the predictors of PH-LHD outcomes. Then, through two prospective multinational cohort registries, we investigated 1) the spectrum of PH in SSA; 2) the clinical profile and 6 months outcome of PH-LHD; 3) the role of electrocardiogram for diagnosing PH and 4) its prognostic role in heart failure (HF). PH was diagnosed by echocardiography in the context of clinical suspicion. Results: In high income countries, PH-LHD is almost invariably associated with increased mortality risk, but the effects on hospitalization are yet to be fully characterized. All groups of PH are found in SSA with LHD being the major cause. PH-LHD affects young people and is predominantly due to HF and rheumatic valvular heart disease. In these patients, left atrium size and tricuspid annular plan excursion are predictors of pulmonary pressures, and PH-LHD predicts short term hospitalization but not mortality. A normal electrocardiogram is very rare in patients with PH, but electrocardiogram criteria of right ventricular strain are rather rare and non-specific. Similarly, electrocardiogram abnormalities are frequent among Africans with HF, some have prognostic value for mortality risk. Conclusion: PH-LHD is the most common form of PH in SSA, with affected patients presenting with advanced disease, and it is associated with adverse outcomes. ECG abnormalities are prevalent in both PH and HF, but few of these abnormalities have prognostic value for mortality risk. Evaluating the efficacy and safety of low-cost and available drugs in reducing HF hospitalizations in PH-LHD is a key future priority. Improving early diagnosis of PH should also be encouraged.

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