Year: 2009
Type: dissertation
Abstract: Coronary artery disease is the leading cause of death in the western world today. Although\ninduction of angiogenesis would appear to be an ideal therapeutic strategy, clinical trials of proangiogenic\nfactors have proved disappointing. Angiogenesis is a complex process involving many\nsignaling pathways and mediators, and further insights into the underlying cellular and molecular\nmechanisms are urgently needed. Here, we used two mouse models, systemic hypoxia and\nmyocardial infarction (MI), to study the effects of hypoxia on angiogenesis in the myocardium,\nand the cellular and molecular mechanisms involved.\nHypoxia-inducible factor-1α (HIF-1α) is an important transcriptional regulator of angiogenesis.\nSmall ubiquitin-related modifier-1 (SUMO-1) has been shown to stabilize transcription factors\nand modulate their activity. In our mouse model of systemic hypoxia, we showed that SUMO-1\nexpression is enhanced by hypoxia in brain and heart. Furthermore, SUMO-1 co-localizes and\ndirectly interacts with HIF-1α under hypoxic conditions, indicating that hypoxia-mediated\nincreases in SUMO-1 expression could modulate HIF-1α function.\nWe combined our mouse model of systemic hypoxia with a model of MI and showed that chronic\nhypoxia protects the heart from infarct injury and promotes angiogenesis. A proteomics analysis\ndemonstrated that protein disulfide isomerase (PDI) is upregulated in the myocardial capillary\nendothelial cells of mice exposed to chronic hypoxia. Furthermore, PDI knockdown in\nendothelial cells in vitro increases apoptosis and inhibits migration and adhesion, indicating that\nPDI may play an integral role in angiogenesis.\nEndoglin is a co-receptor for transforming growth factor-β. In our mouse model of MI, we\nshowed increases in endoglin expression in endothelial cells in the heart one week after surgery.\nSimilarly, endoglin expression is increased in endothelial cells in vitro after exposure to hypoxia.\nFurthermore, we showed that hypoxia promotes activation of the endoglin/ALK-1/SMAD1/5 but\nnot the endoglin/ALK-5/SMAD3 signaling pathway in endothelial cells. The induction of this\npathway represents another potential mechanism for regulation of angiogenic responses in\nendothelial cells after MI.\nThe results presented advance our understanding of the complex pathways involved in hypoxiamediated\nangiogenesis in the heart. Our findings could play a role in identifying new strategies\nfor the treatment of ischemic heart disease.
Author: Fei Tian
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2144690014