BET Proteins Could Be Therapeutic Target for COPD Patients with PH, Rat Study Suggests

Inhibition of proteins that regulate gene expression — called BET — were found to ease pulmonary hypertension (PH) in a rat model of chronic obstructive pulmonary disease (COPD), a study reports.

The study, “Inhibition of BET Proteins Reduces Right Ventricle Hypertrophy and Pulmonary Hypertension Resulting from Combined Hypoxia and Pulmonary Inflammation,” appeared in the International Journal of Molecular Sciences.

PH is characterized by changes in the small pulmonary arteries that increase the resistance to blood flow and lead to hypertrophy, or enlargement, of the heart’s right ventricle.

Scientists believe that in COPD patients, who have a higher incidence of PH than the general population, blood vessel alterations could result from chronic hypoxia — lack of sufficient oxygen — as well as inflammation.

Animal studies showed that enzymes called histone deacetylases could be involved in the development and function of pulmonary arterial smooth muscle cells. These enzymes remove a chemical group known as acetyl from proteins bound to DNA to suppress gene expression, or protein production.

Besides PH, other proteins involved in acetylation, or the addition of an acetyl group, such as BET, play a role in pulmonary arterial hypertension. Accordingly, animals given a BET inhibitor showed restored levels of cell survival markers, lowered proliferation of arterial smooth muscle cells, and increased apoptosis — which refers to programmed cell death, as opposed to cell death caused by injury.

These results, the authors said, suggest that the effects of low oxygen on acetylation could be important in blood vessel alterations in COPD, but inflammation could also be a contributor.

Based on this, they hypothesized that BET inhibitors could be effective in controlling PH. Using the inhibitor I-BET151, the investigators studied if BET proteins are involved in the development of right ventricle hypertrophy and PH in a rat model of COPD. Pulmonary inflammation was combined with chronic hypoxia after one week. I-BET151 was administered for seven days.

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Results showed that, regardless of I-BET151 administration, animals receiving the inflammation inducer LPS twice a week had significant changes in lung structure, and that combined inflammation and hypoxia reduced the size and thickened the wall of the lungs’ tiny air sacs, or alveoli.

Animals subjected to both COPD and PH-related stimuli also showed significant increases in right ventricle hypertrophy, systolic pressure, and contraction speed, as well as an elevated hematocrit — which measures the proportion of red blood cells in the blood — compared with controls. High hematocrit correlates with lower pulmonary circulation, impairing blood oxygenation in patients.

Importantly, treatment with I-BET151 lowered right ventricle hypertrophy and systolic pressure, as well as hematocrit, to levels closer to controls.

“Our study describes novel beneficial effects of I-BET151 under conditions of [PH], induced by chronic hypoxia and pulmonary inflammation,” the researchers wrote. “This suggests that such inhibition could be of potential interest for COPD patients with [PH].”

However, they cautioned that further experiments are needed to determine if the benefits of inhibiting BET proteins outweigh their risks before clinical use in patients with PH secondary to COPD — included in group 3 of the World Health Organization’s classification.

Three of the study’s authors are listed as employees of GlaxoSmithKline, which provided the BET inhibitor.