Pregnancy-induced hypertension or preeclampsia (PE) is estimated to affect 5-7% of all pregnancies in the U.S. Despite its position as a leading cause of maternal death and major contributor to maternal and perinatal morbidity, there is no effective drug treatment to prevent PE. At present, the only effective treatment for PE is early delivery. Based on recent studies and on preliminary data presented in this application, we propose that induction of the stress response gene, hemeoxygenase-1 (HO-1), and its catalytic products, carbon monoxide (CO) and bilirubin, may provide a novel therapeutic approach for the treatment of PE. There is mounting evidence that HO-1 and/or its catalytic products confer cytoprotection against cellular injury in response to placental ischemia, an important initiating event in the pathophysiology of PE. In fact, TNF1 mediated cellular damage in placental villous explants can be prevented by up-regulating HO activity. HO pathways have also been shown to inhibit the release of the anti-angiogenic factor, sFlt-1, in several in vitro models. Our preliminary data also indicates that chronic administration of an HO-1 enzyme inducer or a CO releasing molecule significantly attenuates hypertension in two well-established rat models of PE. Based on our preliminary data, we propose to test the central hypothesis that HO-1 and its metabolites, CO and bilirubin, attenuate the blood pressure and renal responses to placental ischemia in pregnant rats by inhibition of sFlt-l production. In addition, we propose that HO-1 derived products improve renal function and decrease total peripheral resistance and blood pressure by inhibiting the placental production of TNF1 and reactive oxygen species (ROS) and attenuating TNF1 and AT1 receptor autoantibody -induced increases in endothelial cell production of endothelin (ET-1). To test this hypothesis, arterial pressure, renal function, and endothelial factors will be examined in a conscious rat model of PE produced by long-term reductions in uterine perfusion pressure (RUPP). In addition to the RUPP model, a sFlt-1 model of PE will be used to determine the interaction between the HO-1 metabolites and sFlt-1, ET-1, and ROS production while in vitro placental explant and endothelial cell culture models will be used to examine the direct interaction of HO-metabolites in hypoxia- mediated induction of TNF, ROS and placental sFlt-1 and TNF induced ET-1 production.
Specific aims are: 1) To test the hypothesis that HO-1 and its metabolites, CO and bilirubin, attenuate the blood pressure, renal, and sFlt-1 responses to placental ischemia in pregnant rats 2) To test the hypothesis that HO-1 and its metabolites, CO and bilirubin, attenuate placental ischemia and/or hypoxia-induced increases in reactive oxygen species and TNF1 3) To test the hypothesis that HO-1 and its metabolites, CO and bilirubin, attenuate TNF1 and AT1 receptor autoantibody- induced increases in ET-1 production 4) To test the hypothesis that the endogenous HO-1 pathway plays a role in regulating renal function and arterial pressure during normal pregnancy and in response to placental ischemia

Public Health Relevance

Hypertension, as seen in preeclampsia (PE), has long been recognized as a major risk factor for cardiovascular diseases, including coronary artery disease, heart failure and stroke, and for ESRD. Despite its position as a leading cause of maternal death and major contributor to maternal and perinatal morbidity, there is no effective drug treatment to prevent PE. Based on preliminary data presented in this application, we propose that induction of hemeoxygenase-1 and its catalytic products, carbon monoxide and bilirubin, may provide a novel therapeutic approach for the treatment of PE.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL108618-02
Application #
8247752
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Mitchell, Megan S
Project Start
2011-04-01
Project End
2015-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
2
Fiscal Year
2012
Total Cost
$373,750
Indirect Cost
$123,750
Name
University of Mississippi Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
George, Eric M; Garrett, Michael R; Granger, Joey P (2014) Placental ischemia induces changes in gene expression in chorionic tissue. Mamm Genome 25:253-61
Warrington, Junie P; Coleman, Kayla; Skaggs, Courtney et al. (2014) Heme oxygenase-1 promotes migration and ?-epithelial Na+ channel expression in cytotrophoblasts and ischemic placentas. Am J Physiol Regul Integr Comp Physiol 306:R641-6
George, Eric M; Warrington, Junie P; Spradley, Frank T et al. (2014) The heme oxygenases: important regulators of pregnancy and preeclampsia. Am J Physiol Regul Integr Comp Physiol 307:R769-77
George, Eric M; Granger, Joey P (2013) Heme oxygenase in pregnancy and preeclampsia. Curr Opin Nephrol Hypertens 22:156-62
Palei, A C; Spradley, F T; Warrington, J P et al. (2013) Pathophysiology of hypertension in pre-eclampsia: a lesson in integrative physiology. Acta Physiol (Oxf) 208:224-33
American College of Obstetricians and Gynecologists; Task Force on Hypertension in Pregnancy (2013) Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy. Obstet Gynecol 122:1122-31
George, Eric M; Bidwell, Gene L (2013) STOX1: a new player in preeclampsia? Hypertension 61:561-3
Brewer, Justin; Liu, Ruisheng; Lu, Yan et al. (2013) Endothelin-1, oxidative stress, and endogenous angiotensin II: mechanisms of angiotensin II type I receptor autoantibody-enhanced renal and blood pressure response during pregnancy. Hypertension 62:886-92
George, Eric M; Hosick, Peter A; Stec, David E et al. (2013) Heme oxygenase inhibition increases blood pressure in pregnant rats. Am J Hypertens 26:924-30
Warrington, Junie P; George, Eric M; Palei, Ana C et al. (2013) Recent advances in the understanding of the pathophysiology of preeclampsia. Hypertension 62:666-73

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