Cardiovascular Drug Discovery & Therapy (Track)


Iman Ahmed Abdelaziz and Fatima Mraiche

College of Pharmacy, Qatar University, Doha, Qatar


Background: The Na+/H+-exchanger isoform 1 (NHE1) is a ubiquitously expressed housekeeping glycoprotein that functions to regulate intracellular pH. Enhanced NHE1 expression/activity has been implicated in the pathogenesis of cardiac hypertrophy both in vivo and in vitro. Although cardiac hypertrophy itself is considered a predisposing factor to heart failure, the cellular mechanism by which NHE1 induces cardiac hypertrophy remains unknown. Recent reports have suggested that transgenic mice expressing active NHE1 induce a >1500 fold gene expression of osteopontin (OPN). Osteopontin (OPN), a component of the extracellular matrix, has also been associated with myocardial dysfunction.

Objectives: To further understand whether NHE1 induced cardiac hypertrophy is regulated by the expression of OPN in neonatal rat ventricular cardiomyocytes (NRVMs).

Methodology: NRVMs were infected with adenoviruses expressing active NHE1, OPN, or both NHE1 and OPN in the presence or absence of NHE1 inhibitor (EMD87850) and characterized for cardiac hypertrophy.

Results: NHE1 activity in NRVMs infected with NHE1 and OPN was increased vs. control (GFP infected NRVMs) or NRVMs infected NHE1 alone (163.1 +/- 19.5% NHE1 and OPN infected vs. 114.7 +/- 9.5% NHE1 infected NRVMs (P<0.05)). Furthermore, in the presence of both NHE1 and OPN, cell area, which serves as a parameter of cardiac hypertrophy, was significantly increased vs. control (100 +/- 6.0% GFP infected NRVMs vs. 158.9 +/- 2.2% NHE1 and OPN infected NRVMs). However, cell area was not significantly different between NRVMs infected with NHE1 (155.5 +/- 3.4%) vs. NRVMs infected with OPN and NHE1. NHE1 activity as well as cell area in NRVMs infected with NHE1 and OPN were significantly reduced in the presence of EMD87850, an NHE1 inhibitor.

Conclusion: Our findings imply that OPN mediates NHE1-induced cardiac hypertrophy through the enhancement of NHE1 activity. Further studies in the presence of siRNA OPN are required to investigate whether the down regulation of OPN is capable of attenuating NHE1-induced cardiac hypertrophy.

Keywords: Neonatal rat ventricular cardiomyocytes, cardiac hypertrophy, Na+/H+ exchanger, osteopontin