Indiana University-Purdue University Indianapolis (IUPUI) / HIV-associated cardio-pulmonary vascular pathologies such as coronary artery disease, pulmonary hypertension and emphysema remain a major issue in the HIVinfected population even in the era of antiretroviral therapy (ART). The continued production of HIV encoded pro-apoptotic protein, such as Nef in latently HIV-infected cells is a possible mechanism for vascular dysfunction underlying these diseases. HIVNef persists in two compartments in these patients: (i) extracellular vesicles (EV) of plasma and bronchoalveolar lavage (BAL) fluid and (ii) PBMC and BAL derived cells. Here I demonstrate that the presence of HIV-Nef protein in cells and EV is capable of stressing endothelial cells by inducing ROS production leading to endothelial cell apoptosis. HIV-Nef protein hijacks host cell signaling by interacting with small GTP binding protein Rac1 which activates PAK2 to promote the release of pro-apoptotic cargo containing EV and surface expression of pro-apoptotic protein Endothelial Monocyte Activating Polypeptide II (EMAPII). Using this mechanism, Nef protein robustly induces apoptosis in Human Coronary Artery Endothelial Cells and Human Lung microvascular endothelial cells. Endothelial specific expression of HIV-Nef protein in transgenic mice was sufficient to induce vascular pathologies as evidenced by impaired endothelium mediated vasodilation of the aorta and vascular remodeling and emphysema like alveolar rarefaction in the lung. Furthermore, EV isolated from HIV patients on ART was capable of inducing endothelial apoptosis in a Nef dependent fashion. Of therapeutic interest, EMAPII neutralizing antibodies to block EMAPII mediated apoptosis and statin treatment to ameliorate Nef induced Rac1 signaling was capable of blocking Nef induced endothelial stress in both in vivo and in vitro. In conclusion, HIV-Nef protein uses a Rac1-Pak2 signaling axis to promote its dissemination in EV, which in turn induces endothelial cell stress after its uptake.

Indiana University-Purdue University Indianapolis (IUPUI) / Background: Firefighters are exposed to carcinogens, toxic agents, and other risks for cancer and cardiovascular disease. Research shows that aero-digestive and genitourinary cancers are in excess among firefighters compared to the general population. Studies examining excess cardiovascular mortality are inconsistent. Limited data exist on chronic disease mortality, risk factor profiles, and barriers to a healthy lifestyle among firefighters at the local level. Purpose: This project examines the relationship between firefighting and chronic disease mortality, determines trajectories of cardiovascular risk factors in a cohort of new firefighters, and studies the relationship between barriers to weight management and firefighter health characteristics. Methods: This study used death certificate data from the Indiana State Department of Health and clinical data from a large occupational medical practice serving firefighters. Regression techniques were used to examine excess mortality among firefighters compared to non-firefighters, evaluate changes in cardiovascular disease risk factors among new firefighters over time, and explore correlates of risk factors and barriers to weight management among overweight and obese firefighters. Results: The odds of death due to malignant cancers were significantly higher among firefighters than non-firefighters (OR, 1.19; 95% CI, 1.08-1.30). Body mass index, total cholesterol, LDL cholesterol, and triglyceride levels increased significantly (p<0.001) while HDL cholesterol levels decreased (p<0.001) from baseline during the first 10 years of the firefighter’s career. Overweight firefighters who were “ready to begin a weight management program” were more likely to identify ‘‘lack of knowledge about weight management,’’ ‘‘lack of access to exercise opportunities,’’ and ‘‘eating helps me cope with stress’’ as barriers, and report a greater number of barriers to weight management. Older firefighters were less likely to identify or report one or more barriers to weight management. Conclusion: These studies suggest the importance of early-career and targeted cardiometabolic health and cancer prevention strategies to reduce chronic disease morbidity and mortality among firefighters. / 2021-06-28

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21003号 / 医博第4349号 / 新制||医||1028(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 山下 潤, 教授 木村 剛, 教授 小西 靖彦 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

付記する学位プログラム名: グローバル生存学大学院連携プログラム / 京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21670号 / 医博第4476号 / 新制||医||1035(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 今中 雄一, 教授 佐藤 俊哉, 教授 川村 孝 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Background: The use of evidence-based medications for the management of cardiovascular disease (CVD) is low worldwide. A key strategy to improving use of medications is to understand the barriers to their use. This thesis aims to identify barriers that may influence use of these medications in high, middle, and low income countries. Data on barriers in low and middle income countries are especially lacking. We postulate that in those settings lack of availability and affordability of proven medications are key barriers to medication use. Methods: We initially systematically reviewed the literature on barriers to medication use. Since data on these barriers for the management of CVD are sparse, the review included studies focused on hypertension, because it is the leading risk factor for CVD. Baseline data from the PURE study were then used to investigate whether availability and affordability of medications influence their use for secondary prevention of CVD. PURE is a prospective study that recruited adults between the ages of 35 to 70 years from 17 high, middle, and low income countries. Availability and affordability of medications were documented for each country income group, and the associations between these two potential barriers and medication use was explored after accounting for other factors that may influence medication use. Results: The review showed that in high income countries, non-healthcare system related factors, such as lack of knowledge and motivation, were more commonly reported as barriers, whereas in low and middle income countries healthcare system factors were most commonly reported as barriers to hypertension management. However, very few studies were conducted in low and middle income countries and so there is limited information on whether availability and affordability of medications affect their use. Results from the PURE study indicate that medications recommended for the secondary prevention of CVD were often not available and when available, they were not affordable for a high proportion of individuals in low and middle income countries. Lack of availability and low affordability were strongly associated with medication use in these settings. Conclusions: Barriers to medication use are context specific and interventions to improve use should be tailored to barriers depending on the setting. In high income countries where the medications are usually available and affordable interventions should target knowledge and motivation barriers. In low and middle income countries, the focus should be on healthcare system interventions to improve the availability and affordability of medications. / Dissertation / Doctor of Philosophy (PhD)

Cardiovascular disease is a significant health crisis, representing 32% of deaths worldwide in 2019. Vascular calcification (VC), a major contributor to cardiovascular disease, is a regulated biomineralization process whose exact mechanisms are unknown. Additionally, vascular smooth muscle cells (VSMCs) significantly contribute to VC by undergoing a phenotypic switch and differentiating into osteoblast-like cells. When factors like hypertension cause disturbed laminar flow in the body’s vasculature, the mechanical stress promotes the phenotypic switch and calcification of VSMCs via mechanotransduction. VC is also induced by the Wnt pathway, which is activated via mineral imbalance and mechanical stimulation. However, the exact mechanisms behind mechanotransduction in relation to VC, Wnt, and VSMC differentiation are unknown. If uncovered, knowledge of the mechanisms may be used to create effective treatments for VC.

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