Effect of Nitric Oxide and Reactive Oxygen Species on Cardiac Remodeling in Hypoxic Fetal Hearts
AuthorEvans, LaShauna Chante
AdvisorThompson, Loren P.
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AbstractIntrauterine hypoxia increases the rate of fetal morbidity and mortality and compromises cardiovascular function by mechanisms incompletely understood. NO is an important molecule in the regulation of cardiovascular function. Increases in NO levels have been attributed to either cardiac injury or cardioprotection, depending on the condition of study. NO is generated by NOS. In this study, we have shown that by exposing the fetus to low oxygen, NO synthesis in fetal left ventricles is increased via upregulation of iNOS. Other molecular pathways, such as the generation of ROS, are also activated by conditions of chronic hypoxia. Excessive ROS levels have been shown to cause injury to the heart by mutating DNA, inactivating proteins, and inducing lipid peroxidation. Oxidative and nitrosative stress in adult hearts have been shown to decrease myocardial function, which can be restored by antioxidants. This is the first study to demonstrate increased oxidative and nitrosative stress in the fetal heart during intrauterine hypoxia. Additionally, we looked at the effect of hypoxia on downstream proteins involved in cardiac remodeling of the extracellular matrix, such as matrix metalloproteinases, collagen, and pro-apoptotic indices. We reported that maternal hypoxia increased protein expression of MMP9 and collagen accumulation, but decreased caspase 3 protein/activity and DNA fragmentation. These results indicate that chronic hypoxia upregulates NO and ROS generation via iNOS. This suggests that, under low oxygen conditions, the fetal heart may be susceptible to injury when reactive molecules such as ROS and NO are elevated. The overall study provides the basis for the novel concept that upregulation of the iNOS pathway during chronic hypoxia is an important response of the fetus to hypoxic stress. This is likely to have both an immediate impact on fetal cardiac function, as well as lasting effects on the offspring due to programming.
DescriptionUniversity of Maryland, Baltimore. Physiology. Ph.D. 2012
Keywordfetal growth restriction
Reactive Oxygen Species