Cardiovascular Drug Discovery & Therapy (Track)

β-CATENIN/TESCALCIN SIGNALING AS NOVEL TARGET FOR HYPEROXIA-INDUCED PULMONARY HYPERTENSION AND RIGHT VENTRICULAR HYPERTROPHY

Yong Bao Ronald Zambrano, Deepthi Alapati and Shu Wu

Pediatrics, Batchelor Children Research Institute, University of Miami School of Medicine, Miami, Florida, USA

Abstract

Background: Tescalcin (Tesc), also known as calcineurin B homologous 3 (CHP3) plays an important role in heart development, cardiac myocyte proliferation and hypertrophy. β-catenin signaling is one of the most important pathways regulates physiological heart development as well as pathological cardiac hypertrophy. Recent studies have linked Tesc with E-cadherin/β-catenin signaling in mouse heart development and congenital cardiac defect. However, whether β-catenin/Tesc signaling plays a role in hyperoxia-induced heart injury and right ventricular hypertrophy (RVH) remains unknown.

Objective: To determine if β-catenin/CBP signaling inhibitor, ICG001 (ICG), prevents hyperoxia-induced Tesc expression and RVH in neonatal rats.

Design/Methods: Rat pups were randomized within 24 h after birth to: room air (RA)+placebo (PL); RA+ICG; 90% O₂+PL and 90% O₂+ICG. Pups received PL or ICG (10mg/kg) by daily ip injection during continuous RA or O₂ exposure. On day 14 we assessed right ventricular systolic pressure (RVSP), as an index for pulmonary hypertension (PH), and RVH. Expressions of Tesc and Wnt inducible signaling protein 1 (WISP1), a known β-catenin target gene, were assessed by qRT-PCR and Western blot, and these were normalized to β-actin, one of the housekeeping genes. N=5/group; Data are expressed as Mean±SD and analyzed by ANOVA.

Results: RVSP and RVH were increased in O₂+PL group, and these were correlated with significantly increased expressions of Tesc RNA and protein in the RV. There was also a mild increase of Tesc protein expression in the LV in the O₂+PL group. However, treatment with ICG significantly decreased RVSP, RVH and expressions of Tesc RNA and protein in the RV during hyperoxia (table). Similarly, WISP1 was increased by hyperoxia but decreased by ICG in the RV (table).

	RA+PL	O2+PL	RA+ICG001	O2+ICG001	P values
RVSP	12±0.9	22±0.7*	12±0.9	17±0.6#	*P<0.001 #P<0.001
RVH	0.34±0.04	0.53±0.03*	0.32±0.04	0.36±0.03#	*P<0.01 #P<0.001
RV-Tescalcin RNA (Fold)	1.0	2.0*	1.1	-1.1#	*P<0.05 #P<0.001
RV-Tescalcin Protein (Fold)	1.0	2.8*	2.1	1.3#	*P<0.01 #P<0.01
LV-Tescalcin RNA (Fold)	1.0	1.4*	-5.1	-2.5#	*P=0.72 #P<0.05
LV-Tescalcin Protein (Fold)	1.0	1.4*	1.0	1.1#	*P<0.05 #P=0.05
RV-WISP1 RNA (Fold)	1.0	6.2*	3.9	2.3#	*P<0.001 #P<0.05

^*compared to RA+PL; ^#compared to O₂+PL

Conclusion: β-catenin-Tescalcin signaling plays an important role in hyperoxia-induced PH and RVH. Thus, targeting this pathway may be a novel strategy for the prevention and treatment of RVH and PH.