Exposure to chronic hypoxia (CH) occurs with many pulmonary diseases and results in the development of pulmonary hypertension. Studies from our lab and others demonstrated a key role for the transcription factor, hypoxia-inducible factor-1 (HIF-1) in the development of hypoxic pulmonary hypertension. It is well recognized that expression of HIF-1a, the oxygen-sensitive subunit of HIF-1, correlates with hypoxic induction of genes encoding factors implicated in development of pulmonary hypertension, including endothelin-1 (ET-1), a potent vasoconstrictive and mitogenic agent. During the previous funding period, we defined several mechanisms by which CH and ET-1 alter pulmonary vasomotor tone. Recently, our studies revealed a new paradigm where ET-1 regulates HIF-1 expression. Our preliminary data show that ET-1 increased expression of the oxygen-sensitive 1 subunit of HIF-1, HIF-1a, in pulmonary arterial smooth muscle cells (PASMCs), even under normoxic conditions, and reduced expression of prolyl hydroxylases, key enzymes that are responsible for targeting HIF-1a for rapid degradation. These data suggest that while activation of HIF-1 by hypoxia in endothelial cells might cause elevated ET-1 production, subsequent ET-1 signaling in PASMCs contributes to maintained upregulation of HIF-1, creating a positive feedback, or feed-forward, process. Conversely, an elevation in ET-1 levels, as occurs in numerous disease states, may result in increased HIF-1 expression in the absence of associated hypoxia. Based on these new findings, we hypothesize that during moderate hypoxia, increased pulmonary ET-1 production and activation of ET-1 receptors on PASMCs leads to a positive feedback, or feed- forward, mechanism of HIF-11 protein accumulation and enhanced HIF-1-dependent gene transcription. This results in alterations in PASMC function which contribute to the development of pulmonary hypertension. To test this hypothesis, we will use a combination of techniques including transgenic animals, microfluorescence measurements, whole-cell patch-clamp, and molecular biology, to accomplish the following Specific Aims: 1) determine whether ET-1 derived specifically from endothelial cells is required for and/or accelerates HIF-dependent pathophysiological effects of CH in the pulmonary circulation;2) elucidate the mechanism(s) by which ET-1 modulates HIF-1 expression and 3) determine whether HIF-1 is the downstream effector molecule mediating hypoxia- induced alterations in PASMC homeostasis.
The experiments in this proposal will explore cellular mechanisms involved in the development of pulmonary hypertension, a devastating disease with limited treatment options. Understanding the cellular changes that occur in the pulmonary vasculature with development of pulmonary hypertension is key to advancing treatment and therapeutic options.
|Shimoda, Larissa A; Laurie, Steven S (2014) HIF and pulmonary vascular responses to hypoxia. J Appl Physiol (1985) 116:867-74|
|Shimoda, Larissa A; Laurie, Steven S (2013) Vascular remodeling in pulmonary hypertension. J Mol Med (Berl) 91:297-309|
|Pisarcik, Sarah; Maylor, Julie; Lu, Wenju et al. (2013) Activation of hypoxia-inducible factor-1 in pulmonary arterial smooth muscle cells by endothelin-1. Am J Physiol Lung Cell Mol Physiol 304:L549-61|
|Wang, Jian; Shimoda, Larissa A; Sylvester, J T (2012) Ca2+ responses of pulmonary arterial myocytes to acute hypoxia require release from ryanodine and inositol trisphosphate receptors in sarcoplasmic reticulum. Am J Physiol Lung Cell Mol Physiol 303:L161-8|
|Abud, Edsel M; Maylor, Julie; Undem, Clark et al. (2012) Digoxin inhibits development of hypoxic pulmonary hypertension in mice. Proc Natl Acad Sci U S A 109:1239-44|
|Luke, Trevor; Maylor, Julie; Undem, Clark et al. (2012) Kinase-dependent activation of voltage-gated Ca2+ channels by ET-1 in pulmonary arterial myocytes during chronic hypoxia. Am J Physiol Lung Cell Mol Physiol 302:L1128-39|
|Sylvester, J T; Shimoda, Larissa A; Aaronson, Philip I et al. (2012) Hypoxic pulmonary vasoconstriction. Physiol Rev 92:367-520|
|Shimoda, Larissa A; Polak, Jan (2011) Hypoxia. 4. Hypoxia and ion channel function. Am J Physiol Cell Physiol 300:C951-67|
|Weigand, Letitia; Shimoda, Larissa A; Sylvester, J T (2011) Enhancement of myofilament calcium sensitivity by acute hypoxia in rat distal pulmonary arteries. Am J Physiol Lung Cell Mol Physiol 301:L380-7|
|Shimoda, Larissa A; Undem, Clark (2010) Interactions between calcium and reactive oxygen species in pulmonary arterial smooth muscle responses to hypoxia. Respir Physiol Neurobiol 174:221-9|
Showing the most recent 10 out of 18 publications