A Novel H2 Relaxin B-Chain-Only Peptide Variant B7-33 Improves The Pathophysiology Of Placental Ischemia In The Reduced Uterine Perfusion Pressure Rat Model Of Preeclampsia
Abstract Body: Background: Preeclampsia (PE) is a hypertensive pregnancy disorder, which occurs in approximately 10% of all gestations. The literature suggests the potential therapeutic role of H2 relaxin in PE. A novel H2 relaxin B-chain-only peptide variant B7-33 (27 amino acids without any disulfide bonds) has recently been developed. Objective: The goal of this study was to test the hypothesis that a novel H2 relaxin B-chain-only peptide variant B7-33 could improve the pathophysiology of placental ischemia in the Reduced Uterine Perfusion Pressure (RUPP) rat model of PE. Methods: The efficacy of B7-33 was evaluated in the RUPP model as described previously. RUPP rats are randomly assigned to 4 groups (N=8/group): 1) vehicle, 2) B733; 3) B733-Fc; and 4) B733-HSA. Rats are dosed twice weekly (i.v.) from GD10 to GD 20. On GD 18, rats are anesthetized with isoflurane, and carotid arterial catheters are inserted into the carotid artery, tunneled under the skin, and externalized at the back of the neck. On the following day, mean arterial pressure (MAP) is monitored with a pressure transducer (Cobe III Tranducer CDX Sema) and recorded continuously for 30 min. On GD18, uterine artery resistance index (UARI) of rats is measured by Doppler sonography. The nitric oxide bioavailability, soluble fms-like tyrosine kinase-1 (sFlt-1), and TNF-α) were measured by commercially available kits. Statistical comparisons were performed using analysis of variance with Duncan’s post hoc test. Results: The RUPP rats have increased MAP (122.2 ± 8.1 mm Hg), plasma TNF-α (223 ±11.4 pg/mL), and plasma sFlt-1(863 ±18.2 pg/mL) along with decreased NO index (14±2 µM) compared to normal pregnancy: MAP (102 ± 5.2 mm Hg); plasma TNF-α (28 ± 4.1 pg/mL); plasma sFlt-1(244 ± 9.4 pg/mL) and NO index (26 ±4.1 µM). Treatment with B733 and B7-33 fusion proteins significantly (*p<0.05) lowers MAP, plasma TNF-α, and plasma sFlt-1 and increased NO index back to that of normal pregnancy. The B7-33 data are consistent with earlier data with serelaxin in the RUPP model. All fusions tested ameliorate hypertension in the RUPP animals. B7-33 normalizes BP and proteinuria in the DOCA rat model of preE. Conclusion: The conclusion of the study is that both B7-33 and B7-33 fusion proteins demonstrate efficacy in attenuating the symptoms of PE including hypertension and inflammation in RUPP model. We conclude that B7-33 is an ideal candidate for development as a novel therapeutic in preE.
Pantho, Ahmed F
( Artemis Biotechnologies LLC
, Temple
, Texas
, United States
)
Hossain, Mohammed
( University of Melbourne
, Melbourne
, Victoria
, Australia
)
Uddin, Mohammad
( TAMU SOM BSWH
, Temple
, Texas
, United States
)
Amaral, Lorena
( MEDICAL CENTER- UMMC
, Jackson
, Mississippi
, United States
)
Campbell, Nathan
( University of Mississippi Medical C
, Jackson
, Mississippi
, United States
)
Afroze, Syeda
( Artemis Biotechnologies LLC
, Temple
, Texas
, United States
)
Vora, Niraj
( Baylor Scott and White Hospital
, Leander
, Texas
, United States
)
Kuehl, Thomas
( Artemis Biotechnologies LLC
, Temple
, Texas
, United States
)
Lindheim, Steven
( Baylor Scott and White Hospital
, Leander
, Texas
, United States
)
Lamarca, Babbette
( UNIVERSITY MISSISSIPPI MEDICAL CTR
, Jackson
, Mississippi
, United States
)
Bathgate, Ross
( University of Melbourne
, Melbourne
, Victoria
, Australia
)
Author Disclosures:
Ahmed F Pantho:DO NOT have relevant financial relationships
| Mohammed Hossain:No Answer
| Mohammad Uddin:DO NOT have relevant financial relationships
| Lorena Amaral:DO NOT have relevant financial relationships
| Nathan Campbell:DO NOT have relevant financial relationships
| Syeda Afroze:No Answer
| Niraj Vora:No Answer
| Thomas Kuehl:No Answer
| Steven Lindheim:No Answer
| Babbette Lamarca:DO NOT have relevant financial relationships
| Ross Bathgate:No Answer