The rapid growth of smooth muscle cells in pulmonary arteries causes vasoconstriction and pulmonary arterial hypertension (PAH). Now, researchers found that the same drugs that inhibit cancer cell growth may also be effective in treating PAH.
The study, “Inhibition of ubiquitin proteasome function prevents monocrotaline-induced pulmonary arterial remodeling,” appeared in the journal Life Sciences.
Cells have a method — known as the ubiquitin proteasome system (UPS) — to degrade damaged or unnecessary proteins. In cancer, over-activation of UPS degrades proteins whose function is to restrain cell growth. As a result, cells grow out of control. Therefore, proteasome inhibitors are effective in some cancers and have been approved by the U.S. Food and Drug Administration (FDA) for clinical use.
In a Petri dish, proteasome inhibition prevents the growth of pulmonary arterial smooth muscle cells (PASMCs), just like in cancer cells. This observation led researchers to investigate the effect of two proteasome inhibitors, MG-132 and bortezomib, in suppressing vascular constriction in rats with PAH.
A group of rats received an injection of monocrotaline (MCT), which induces several characteristics associated with PHA. Researchers then assessed several parameters, including the right ventricular systolic pressure (RVSP), the right ventricle hypertrophy index (RVHI) and the percentage of medial wall thickness (%MT).
Researchers found that treatment with MG-132 or bortezomib prevented MCT-induced PAH in rats. Treated PAH rats showed reduced values of RVSP (50.26 mmHg to 37.17 mmHg) and of RVHI (0.63 to 0.46-0.48).
By looking at pulmonary tissue of MCT-treated rats, researchers observed a significant increase in the %MT due to the growth of PASMC. But the proteasome inhibitors MG-132 and bortezomib significantly prevented this effect (52.07 to 37.82-39.03). These same drugs also reduced pulmonary arterial remodeling.
“These results indicate that proteasome inhibition dramatically inhibited the pulmonary arterial remodeling by suppressing the proliferation of PASMCs,” the team concluded.
From previous studies in cancer cells, researchers knew that UPS degrades PTEN, a protein that prevents cell growth. Now, they found that PTEN was also significantly reduced in the lungs of PAH rats. Importantly, treatment with protease inhibitors recovered the levels of PTEN, with a subsequent inhibition of PASMCs growth.
Overall, based on this study, the team concluded that “[i]nhibition of proteasome function ameliorates pulmonary arterial remodeling by suppressing UPS-mediated PTEN degradation.” The researchers believe that UPS might be a novel target for PAH prevention and treatment.
Since proteasome inhibitors have FDA approval, clinical trials in PAH patients may begin soon.