Tetramethylpyrazine Inhibits Hypoxia-Induced Pulmonary Vascular Leakage in Rats via the ROS-HIF-VEGF Pathway

Abstract

Tetramethylpyrazine (TMP) is a reactive oxygen species (ROS) antagonist that has potent properties for the treatment of a variety of vascular diseases, such as ischemic stroke and pulmonary hypertension secondary to chronic obstructive pulmonary diseases. However, there are few data about the role of TMP in hypoxia-induced pulmonary vascular leakage. This study examined the effect of TMP on hypoxia-induced pulmonary vascular leakage and the underlying mechanisms. Rat pulmonary microvascular endothelial cells (RPMVECs) treated with TMP or not were subjected to hypoxic or normoxic conditions for 24 h, and the monolayer permeability, intracellular ROS, hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) proteins levels were determined. Additionally, rats administrated TMP were exposed to hypobaric hypoxia to evaluate the effect of TMP in vivo by measuring lung water content, pulmonary vascular leakage into the lungs and immunohistochemistry for HIF-1α and VEGF. Hypoxia was found to cause a significant increase in RPMVEC monolayer permeability and intracellular ROS, HIF-1α and VEGF protein levels. Treatment with TMP decreased the hypoxia-induced RPMVEC monolayer permeability and attenuated the elevation of ROS, HIF-1α and VEGF protein levels. TMP-treated animals showed less pulmonary vascular leakage and HIF-1α and VEGF expression compared with those exposed to hypoxia alone. These observations supported that TMP inhibited the increase in pulmonary vascular permeability induced by hypoxia. The underlying mechanisms may be related to the scavenging of intracellular ROS and the suppression of hypoxia-induced upregulation of HIF-1α and VEGF proteins.

PI3K and ERK-Induced Rac1 Activation Mediates Hypoxia-Induced HIF-1α Expression in MCF-7 Breast Cancer Cells

“…An earlier report showed that thymosin beta-4-induced HIF-1α stabilization in human cervical tumor cells is ROS-dependent [53]. However, the mechanism whereby ROS influences HIF-1α expression has not been described.…”

Tetramethylpyrazine promotes the proliferation and migration of brain endothelial cells

“…TMP also decreased the expression of intracellular adhesion molecule-1 and heat shock protein 60, suggesting its anti-inflammatory role in endothelial cells (9). As a reactive oxygen species antagonist, TMP protected the rat pulmonary microvascular endothelial cells from hypoxia and TMP-treated animals demonstrated less pulmonary vascular leakage compared with those exposed to hypoxia alone (10). It was also reported that TMP, or its derivatives, suppressed the apoptosis of HUVECs induced by hydrogen peroxide (11).…”

Mechanisms and Clinical Application of Tetramethylpyrazine (an Interesting Natural Compound Isolated from Ligusticum Wallichii): Current Status and Perspective

“…Clinical and laboratory studies on herbal medicine draw special attention to ROS-pathway-mediated injury in CVDs [ 19 ]. The scavenging ROS function of TMP on hypoxia induced pulmonary vascular leakage had been explored [ 20 ], and H 2 O 2 -induced human umbilical vein endothelial cells (HUVECs) were also employed to evaluate protective effect of TMP on oxidative stress, as well as its antiapoptotic properties [ 21 ]. By testing its effect on C2C12 myotube, Gao and his coworkers [ 22 ] reported that TMP could restrain mitochondrial ROS generation and upregulate the expression of PGC1, NRF1, and Tfam, which reflects mitochondrial biogenesis.…”