Inhibiting a Specific Molecular Chaperone May Help Treat PAH, Animal Study Suggests
Inhibiting the molecular chaperone heat shock protein 90 (HSP90) may be a promising therapeutic approach in pulmonary arterial hypertension (PAH), according to an animal study developed by researchers at the Second Military Medical University in China.
The study, “Inhibition of heat shock protein 90 improves pulmonary arteriole remodeling in pulmonary arterial hypertension,” published in Oncotarget, reveals that HSP90 inhibition reduces vascular remodeling and arterial smooth muscle cell proliferation in a rat model of pulmonary hypertension (PH).
HSP90 is a protein involved in a variety of physiological cellular processes, but can also be involved in pathologies such as cancer. Although the role of HSP90 in PAH remains unclear, recent studies have demonstrated that inhibiting HSP90 with 17-AAG (17-allylamino-17-demethoxygeldamycin) can attenuate the formation of atherosclerotic plaques by decreasing inflammatory responses and suppress migration and proliferation of vascular smooth muscle cells.
Since PAH is characterized by extensive proliferation of pulmonary artery smooth muscle cells, the muscle cells that surround the pulmonary arteries, the researchers aimed to explore the role of HSP90 in PAH and whether targeting HSP90 could have any therapeutic utility.
Zhi-Yun Xu and colleagues examined plasma samples from 27 coronary heart disease (CHD) patients with PAH, 39 CHD patients without PAH, and 23 healthy controls. The levels of HSP90 were significantly higher in PAH patients, compared to those included in CHD-only and control groups.
The researchers also found that the HSP90 levels were significantly higher in lung tissue collected from CDH patients with PAH than in normal lung tissue collected in autopsies. Importantly, HSP90 was found to be expressed in the pulmonary arteriole in 81.8 percent of CHD patients with PAH, but its expression was not found in normal lung tissue samples, suggesting that HSP90 could be involved in the progress of PAH.
Therefore, the investigators assessed whether inhibiting HSP90 with 17-AAG in a rat model of PH could decrease disease progression. Their results showed that 17-AAG decreased the pulmonary arterial pressure in these rats, and did not induce right ventricular hypertrophy, a common consequence of increased blood pressure in the pulmonary arteries.
When analyzing the lung tissue, researchers found that 17-AAG-treated rats had reduced pulmonary artery wall thickness, suggesting that vascular remodeling was improved upon HSP90 inhibition. Also, the migration and proliferation of the pulmonary artery smooth muscle cells, as well as the PH-derived inflammatory response, were attenuated upon 17-AAG treatment.
These results suggest that HSP90 may be a promising therapeutic target for the treatment of PAH patients.