Journal Article

Silencing of Sodium–Hydrogen Exchanger 1 Attenuates the Proliferation, Hypertrophy, and Migration of Pulmonary Artery Smooth Muscle Cells via E2F1

Yu, Lunyin, Hales, Charles A.

2011

Overview

We previously found that deficiency of the sodium–hydrogen exchanger 1 (NHE1) gene prevented hypoxia-induced pulmonary hypertension and vascular remodeling in mice, which were accompanied by a significantly reduced proliferation of pulmonary artery smooth muscle cells (PASMCs), and which decreased the medial-wall thickness of pulmonary arteries. That finding indicated the involvement of NHE1 in the proliferation and hypertrophy of PASMCs, but the underlying mechanism was not fully understood. To define the mechanism by which the inhibition of NHE1 decreases hypoxic pulmonary hypertension and vascular remodeling, we investigated the role of E2F1, a nuclear transcription factor, in silencing the NHE1 gene–induced inhibition of the proliferation, hypertrophy, and migration of human PASMCs. We found that: (1) silencing of NHE1 by short, interfering RNA (siRNA) significantly inhibited PASMC proliferation and cell cycle progression, decreased hypoxia-induced hypertrophy (in terms of cell size and protein/DNA ratio) and migration (in terms of the wound-healing and migration chamber assays); (2) hypoxia induced the expression of E2F1, which was reversed by NHE1 siRNA; and (3) the overexpression of E2F1 blocked the inhibitory effect of NHE1 siRNA on the proliferation, hypertrophy, and migration of PASMCs. The present study determined that silencing the NHE1 gene significantly inhibited the hypoxia-induced proliferation, hypertrophy, and migration of human PASMCs via repression of the nuclear transcription factor E2F1. This study revealed a novel mechanism underlying the regulation of hypoxic pulmonary hypertension and vascular remodeling via NHE1.

• Publisher: Oxford University Press,American Thoracic Society
• Subject: Cation Transport Proteins - genetics / Cation Transport Proteins - metabolism / Cell cycle / Cell Hypoxia / Cell Line / Cell Movement / Cell Proliferation / Cell Size / E2F1 Transcription Factor - metabolism / Gene Silencing / Humans / Hypertension / Hypertension, Pulmonary - genetics / Hypertension, Pulmonary - metabolism / Hypertension, Pulmonary - physiopathology / Hypertrophy / Hypoxia / Muscle, Smooth, Vascular - metabolism / Myocytes, Smooth Muscle - metabolism / Na+/H+-exchanging ATPase / Nhe1 gene / Pulmonary arteries / Pulmonary artery / Pulmonary Artery - metabolism / Pulmonary hypertension / RNA, Small Interfering - metabolism / siRNA / Smooth muscle / Sodium-Hydrogen Exchanger 1 / Sodium-Hydrogen Exchangers - genetics / Sodium-Hydrogen Exchangers - metabolism / Transcription factors / Wound healing