Oxygen-sensing protein a potential therapeutic target in PAH: Study
HIF-1alpha may contribute to worse disease; higher levels seen in patients
An oxygen-sensing protein called hypoxia-inducible factor-1alpha, or HIF-1alpha, may contribute to worsening pulmonary arterial hypertension (PAH) and is a possible therapeutic target for people with this rare type of pulmonary hypertension, a study by Chinese scientists found.
According to the researchers, HIF-1alpha may worsen PAH by increasing the uptake of fatty molecules in cells and speeding the degradation of mitochondria, which serve as the powerhouses of cells.
As such, targeting this protein could lead to new treatments for PAH patients, the team noted.
“These findings may provide new insights for the development of therapeutic strategies targeting PAH,” the researchers wrote. Their study involved blood samples from people with PAH and testing in a rat model of the disease.
Titled “PI3K p85[alpha]/HIF-1[alpha] accelerates the development of pulmonary arterial hypertension by regulating fatty acid uptake and mitophagy,” the study was published in the journal Molecular Medicine.
Findings shed light on workings of oxygen-sensing protein HIF-1alpha in PAH
PAH occurs when blood pressure in the lungs is high, leading to symptoms such as shortness of breath, fatigue, and chest pain. It also creates strain on the heart. This is due in part to poorly working mitochondria, which impairs fatty acid metabolism — how these fatty molecules are processed in the body — in a cellular pathway that produces energy.
HIF-1alpha, a protein activated in low oxygen, is thought to play a role in PAH development and the breakdown of fatty acids.
“Despite advances in modern treatment strategies [in PAH] … the prognosis remains unfavorable,” the researchers wrote. “Therefore, understanding the pathogenesis [disease development] of PAH is critical to the development of novel therapeutic approaches.”
Further, the team added, “exploring the regulatory mechanism [underlying the workings of] HIF-1[alpha] … may contribute to the understanding of PAH.”
Despite advances in modern treatment strategies [in PAH] … the prognosis remains unfavorable. … Therefore, understanding the pathogenesis [disease development] of PAH is critical to the development of novel therapeutic approaches.
To that end, the team tested blood samples from 20 adults with PAH — 16 women and four men. Among them, 18 had developed PAH as a complication of congenital heart disease. The other two had idiopathic PAH, meaning that the cause of the disease was unknown. The team also tested samples from 20 healthy people, who served as controls.
Compared with the healthy volunteers, the patients had higher levels of HIF-1alpha. They also had higher levels of proteins involved in fatty acid metabolism, and of markers of mitophagy, a process that eliminates and recycles dysfunctional mitochondria.
In lab-grown pulmonary artery smooth muscle cells, reducing the levels of HIF-1alpha or a signaling protein called PI3K p85alpha caused them to stop growing in number. Such reductions also suppressed mitophagy and reduced the accumulation of damaging reactive oxygen species — pro-oxidant molecules that may damage DNA and other cellular components.
The results also showed that reducing the levels of CD36, one of the proteins involved in fatty acid metabolism, had the opposite effect. This was reversed by adding palmitic acid, the most common saturated fatty acid in the human body. CD36 has also been associated with mitochondrial dysfunction, the scientists noted.
The researchers also used a rat model of PAH for testing. In the rats, a blocker of HIF-1alpha, called 2-methoxyestradiol, or 2ME, reduced signs of PAH, including high blood pressure in the pulmonary arteries, damage to the pulmonary arteries, and the buildup of fats. However, when CD36 was added, the benefits of 2ME disappeared, though the protein inhibited mitophagy.
Another approach, a compound called salidroside that activates a pathway induced by low oxygen, helped rats with PAH by promoting mitophagy. When salidroside was combined with 2ME, the treatment worked even better.
Overall, according to the researchers, “these observations helped to further elucidate the role of HIF-1[alpha] in the pathogenesis of PAH and suggested new potential strategies for the treatment of PAH.”
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