Biomedical Sciences ETDs

Author

Jessica Snow

Publication Date

12-1-2009

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 PKCα/β-dependent ROS generation. Therefore, both mitochondrial ROS and PKCα/β represent potential therapeutic targets in the development of SA-induced PH.

Keywords

pulmonary hypertension, intermittent hypoxia

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Advisor

Resta, Thomas

First Committee Member (Chair)

Walker, Benjimen

Second Committee Member

Kanagy, Nancy

Third Committee Member

Walker, Mary

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