Recent evidence suggests that pulmonary vascular tone is regulated by a complex interaction of vasoactive substances that are locally produced by the vascular endothelium, such as nitric oxide (NO) and endothelin-1 (ET-1). Endothelial injury secondary to increased pulmonary blood flow and/or pressure disrupts these regulatory mechanisms, and is a potential factor in the development of a number of cardiovascular diseases including pulmonary hypertension. However, the mechanisms by which the endothelial dysfunction occurs have not been adequately resolved. We have established a lamb model of pulmonary hypertension secondary to increased pulmonary blood flow. In this model, similar to infants born with ventricular septal defects, there is an increase in the expression of the genes that induce pulmonary vasoconstriction and a reduction in those that induce vasodilation. In the initial funding period we have demonstrated that increased reactive oxygen species (ROS) generation in the pulmonary vessels is associated with the development of pulmonary hypertension and that ROS scavengers normalize the vasodilator response in pulmonary vessels isolated from these lambs. We have also demonstrated that these increases in ROS are associated with decreased NO-signaling. In addition, our new preliminary data indicate that the increased ROS generation correlates with the elevation in the levels of the endogenous NOS inhibitor, asymmetric dimethyl arginine (ADMA) and decreases in the levels of the NOS co-factor tetrahydrobiopterin (BH4). Further, we have obtained evidence that mitochondrial dysfunction, secondary to disruptions of carnitine metabolism, appears to play an important role in the endothelial dysfunction associated with the development of pulmonary hypertension. Thus, in this competitive renewal we plan to elucidate the mechanisms by which mitochondrial dysfunction occurs and elucidate the role played by ADMA in this process. We anticipate that the successful completion of our studies will significantly increase our understanding of the mechanisms underlying the diminished NO-signaling and endothelial dysfunction associated with the development of pulmonary hypertension secondary to increased pulmonary blood flow. Further, our studies may suggest new signaling pathways that may have clinical utility for the treatment of infants and children with pulmonary hypertension.

Public Health Relevance

The incidence of congenital heart defects in the U.S. is ~1 per 100 live births. Approximately 50% of these children require medical and/or surgical attention. The majority of defects requiring treatment are associated with increased pulmonary blood flow. This includes children born with ventricular septal defect, truncus arteriosus, or atrioventricular septal defect. Survival for children born with congenital heart defects has improved because of the development of new diagnostic tools, and advances in surgical techniques and post-operative management. However, these children continue to suffer significant morbidity and late mortality, in part because of abnormal vascular reactivity leading to endothelial dysfunction within the pulmonary circulation. The factors responsible for the development of endothelial dysfunction are incompletely understood. A better understanding of the cellular and molecular mechanisms that underlie the development of endothelial dysfunction will lead to improved survival for newborns, infants, and children with congenital heart defects. Thus, the studies in this proposal to investigate the mechanism for the progressive decrease in NO-Signaling seen in our lamb model of congenital heart disease and increased pulmonary blood flow have the potential to significantly impact the survival of children born with congenital heart defects.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL067841-09
Application #
7792330
Study Section
Special Emphasis Panel (ZRG1-CVS-D (03))
Program Officer
Lin, Sara
Project Start
2002-04-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
9
Fiscal Year
2010
Total Cost
$369,118
Indirect Cost
Name
Georgia Regents University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
de la Vega, Montserrat Rojo; Dodson, Matthew; Gross, Christine et al. (2016) Role of Nrf2 and Autophagy in Acute Lung Injury. Curr Pharmacol Rep 2:91-101
Kovacs, Laszlo; Han, Weihong; Rafikov, Ruslan et al. (2016) Activation of Calpain-2 by Mediators in Pulmonary Vascular Remodeling of Pulmonary Arterial Hypertension. Am J Respir Cell Mol Biol 54:384-93
Song, Shanshan; Jacobson, Krista N; McDermott, Kimberly M et al. (2016) ATP promotes cell survival via regulation of cytosolic [Ca2+] and Bcl-2/Bax ratio in lung cancer cells. Am J Physiol Cell Physiol 310:C99-C114
Sharma, Bal Krishan; Kolhe, Ravindra; Black, Stephen M et al. (2016) Inhibitor of differentiation 1 transcription factor promotes metabolic reprogramming in hepatocellular carcinoma cells. FASEB J 30:262-75
Sun, Xutong; Kellner, Manuela; Desai, Ankit A et al. (2016) Asymmetric Dimethylarginine Stimulates Akt1 Phosphorylation via Heat Shock Protein 70-Facilitated Carboxyl-Terminal Modulator Protein Degradation in Pulmonary Arterial Endothelial Cells. Am J Respir Cell Mol Biol 55:275-87
Rafikova, Olga; Meadows, Mary L; Kinchen, Jason M et al. (2016) Metabolic Changes Precede the Development of Pulmonary Hypertension in the Monocrotaline Exposed Rat Lung. PLoS One 11:e0150480
Rafikov, Ruslan; Sun, Xutong; Rafikova, Olga et al. (2015) Complex I dysfunction underlies the glycolytic switch in pulmonary hypertensive smooth muscle cells. Redox Biol 6:278-86
Lu, Qing; Harris, Valerie A; Rafikov, Ruslan et al. (2015) Nitric oxide induces hypoxia ischemic injury in the neonatal brain via the disruption of neuronal iron metabolism. Redox Biol 6:112-21
Bertero, Thomas; Cottrill, Katherine A; Lu, Yu et al. (2015) Matrix Remodeling Promotes Pulmonary Hypertension through Feedback Mechanoactivation of the YAP/TAZ-miR-130/301 Circuit. Cell Rep 13:1016-32
Black, Stephen M (2015) β3-Adrenoceptor, glutathionylation, and diabetic cardiomyopathy. Focus on ""β3-Adrenoceptor activation relieves oxidative inhibition of the cardiac Na+-K+ pump in hyperglycemia induced by insulin receptor blockade"". Am J Physiol Cell Physiol 309:C283-5

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