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Pulmonary vasoconstrictor reactivity following intermittent hypoxia

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Please use this identifier to cite or link to this item: http://hdl.handle.net/1928/10307

Pulmonary vasoconstrictor reactivity following intermittent hypoxia

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Title: Pulmonary vasoconstrictor reactivity following intermittent hypoxia
Author: Snow, Jessica
Advisor(s): Resta, Thomas
Committee Member(s): Walker, Benjimen
Kanagy, Nancy
Walker, Mary
Department: University of New Mexico. Biomedical Sciences Graduate Program
Subject(s): pulmonary hypertension
intermittent hypoxia
LC Subject(s): Pulmonary hypertension
Anoxemia
Vasoconstrictors
Sleep apnea syndromes
Mitochondria
Rho GTPases
Degree Level: Doctoral
Abstract: Sleep apnea (SA) affects as many as 20% of the adult population in the United States. It elicits intermittent hypoxia (IH) and causes pulmonary hypertension (PH), however the mechanisms of this PH have not been well studied. IH has been shown to cause polycythemia, pulmonary vascular remodeling and increases in vasoconstrictor reactivity. CO2 supplementation may be protective in the development of PH, therefore we assessed effects of IH with and without CO2 supplementation on indices of PH and pulmonary vasoconstrictor reactivity. IH with CO2 supplementation resulted in eucapnic IH (E-IH) and the lack of polycythemia or vascular remodeling. However, E-IH caused significant right ventricular hypertrophy and increased pulmonary vasoconstrictor reactivity, which was mediated by vascular smooth muscle (VSM) Ca2+ sensitization. We, therefore, sought to determine the mechanism of this enhanced vasoconstrictor reactivity by assessing vasoconstriction and VSM Ca2+ responses to the endothelium-derived vasoconstrictor peptide endothelin-1 (ET-1). Given evidence that Rho kinase (ROK), PKC and reactive oxygen species (ROS) contribute to the development of PH, we addressed their respective contributions to augmented pulmonary vasoconstrictor reactivity to ET-1 following E-IH. Interestingly, we found that ROK did not contribute to ET-1-induced pulmonary vasoconstriction. However, PKC- and ROS- dependent signaling is augmented following E-IH and these mediators appear to signal in series, with the mitochondria providing the source of ROS. Furthermore, E-IH augments PKC-dependent ROS generation. Therefore, both mitochondrial ROS and PKC represent potential therapeutic targets in the development of SA-induced PH.
Graduation Date: December 2009
URI: http://hdl.handle.net/1928/10307

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