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 #
5R01HL108618-04
Application #
8601899
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
2014-01-01
Budget End
2014-12-31
Support Year
4
Fiscal Year
2014
Total Cost
$336,375
Indirect Cost
$111,375
Name
University of Mississippi Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
Cunningham Jr, Mark W; Williams, Jan M; Amaral, Lorena et al. (2016) Agonistic Autoantibodies to the Angiotensin II Type 1 Receptor Enhance Angiotensin II-Induced Renal Vascular Sensitivity and Reduce Renal Function During Pregnancy. Hypertension 68:1308-1313
Karumanchi, S Ananth; Granger, Joey P (2016) Preeclampsia and Pregnancy-Related Hypertensive Disorders. Hypertension 67:238-42
Stec, David E; Juncos, Luis A; Granger, Joey P (2016) Renal intramedullary infusion of tempol normalizes the blood pressure response to intrarenal blockade of heme oxygenase-1 in angiotensin II-dependent hypertension. J Am Soc Hypertens 10:346-51
Spradley, Frank T; Palei, Ana C; Granger, Joey P (2016) Differential body weight, blood pressure and placental inflammatory responses to normal versus high-fat diet in melanocortin-4 receptor-deficient pregnant rats. J Hypertens 34:1998-2007
Spradley, Frank T; Sasser, Jennifer M; Musall, Jacqueline B et al. (2016) Nitric oxide synthase-mediated blood pressure regulation in obese melanocortin-4 receptor-deficient pregnant rats. Am J Physiol Regul Integr Comp Physiol 311:R851-R857
LaMarca, Babbette; Amaral, Lorena M; Harmon, Ashlyn C et al. (2016) Placental Ischemia and Resultant Phenotype in Animal Models of Preeclampsia. Curr Hypertens Rep 18:38
Bakrania, Bhavisha; Granger, Joey P; Harmancey, Romain (2016) Methods for the Determination of Rates of Glucose and Fatty Acid Oxidation in the Isolated Working Rat Heart. J Vis Exp :
Sasser, Jennifer M; Murphy, Sydney R; Granger, Joey P (2015) Emerging drugs for preeclampsia--the endothelium as a target. Expert Opin Emerg Drugs 20:527-30
Spradley, Frank T; Palei, Ana C; Granger, Joey P (2015) Increased risk for the development of preeclampsia in obese pregnancies: weighing in on the mechanisms. Am J Physiol Regul Integr Comp Physiol 309:R1326-43
George, Eric M; Stout, Jacob M; Stec, David E et al. (2015) Heme oxygenase induction attenuates TNF-α-induced hypertension in pregnant rodents. Front Pharmacol 6:165

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