Boosting Levels of Tex261 Protein Eases PAH in Rat Study
Scientists found PAH development in rats was linked to lower Tex261 levels
Increasing the levels of the Tex261 protein — either as a preventive or therapeutic approach — eased the symptoms of pulmonary arterial hypertension (PAH) in a rat model of the disease, a new study shows.
These benefits were seen after the scientists had found that PAH development in rats was associated with lower Tex261 protein levels.
The study, “Supplementation with Tex261 provides a possible preventive treatment for hypoxic pulmonary artery hypertension,” was published in the journal Frontiers in Pharmacology.
Tex261 protein is thought to be involved in the transport of cargo inside cells
Pulmonary artery smooth muscle cells (PASMCs) play a key role in vascular remodeling, a key process of lung vessel structural alterations that also involves dysfunction of the inflammatory and immune systems. This promotes blood pressure increase and as a result, the heart’s right ventricle (RV) needs to work harder to pump blood.
The TEX261 gene codes for a protein, also named Tex261, that is thought to be involved in the transport of cargo inside cells. The gene also has been found to regulate cell proliferation (an increase in the number of cells) and death in prostate cancer. However, whether it plays a role in PAH remains unknown.
this study provides a new theoretical basis for elucidating the pathogenesis [disease development] of PAH and potential treatment and prevention targets for PAH
Researchers in China used a rat model of PAH, where administration of a compound called Sugen5416 is combined with exposure to hypoxia (low oxygen levels).
Levels of Tex261 protein and messenger RNA (mRNA; made from DNA and containing the instructions to make Tex261 protein) were significantly reduced in PASMCs and pulmonary arteries under hypoxia. In addition, mRNA levels of Tex261 gradually decreased as exposure to hypoxia increased. Tex261 also lowered with a higher RV mass index (RVMI) and higher RV systolic pressure (RVSP).
Then, the team used small interfering RNAs (siRNAs) — molecules that bind to a specific mRNA targeting it for destruction — to silence production of the Hif-1alpha protein in PASMCs. This reversed the hypoxia-induced Tex261 decrease. Of note, Hif-1alpha is part of a molecule that activates the conversion of DNA into RNA.
“These results suggest that Tex261 is involved in the development of PAH and is regulated by Hif-1α under hypoxia,” the scientists wrote.
Using a similar approach but targeting Tex261 led to a significant increase in the proportion of proliferating cells. In contrast, overproducing Tex261 by using engineered viral vectors (AAV6-Tex261) suppressed cell viability.
‘Tex261 could prevent PAH to some extent’
To first test the preventive potential of Tex261, the researchers infused the rats with AAV6-Tex261 or with a control vector (AAV6-GFP), delivered via the trachea (windpipe) to reach the lungs. Two weeks later, the animals were injected with Sugen5416 and exposed to a normal or hypoxic environment for three more weeks.
Both RVSP and RVMI were significantly lessened in hypoxic rats with high levels of Tex261 compared to controls. In addition, pulmonary vessel walls were thinned and pulmonary artery scarring was reduced with AAV6-Tex261.
“These results indicated that Tex261 could prevent PAH to some extent,” the investigators wrote.
Next, they assessed the therapeutic effects of boosting the levels of Tex261 following PAH induction. After Sugen5416 injection and exposure to hypoxia for three weeks, the animals received AAV6-Tex261 or AAV6-GFP and were exposed to normal levels of oxygen for two more weeks.
While exposure to hypoxia led to a significant increase in RVSP and RVMI, treatment with AAV6-Tex261 significantly reduced both measures. Also, Tex261 overproduction alleviated pulmonary artery remodeling and scarring.
Overall, “this study provides a new theoretical basis for elucidating the pathogenesis [disease development] of PAH and potential treatment and prevention targets for PAH,” the researchers wrote.