Format

Send to

Choose Destination
Antioxidants (Basel). 2018 Oct 26;7(11). pii: E150. doi: 10.3390/antiox7110150.

Effects of Bcl-2/Bcl-xL Inhibitors on Pulmonary Artery Smooth Muscle Cells.

Author information

1
Department of Pharmacology and Physiology, Georgetown University Medical Center, Georgetown University, 3900 Reservoir Road NW, Washington, DC 20007, USA. rybkavladyslava@gmail.com.
2
Department of Pharmacology and Physiology, Georgetown University Medical Center, Georgetown University, 3900 Reservoir Road NW, Washington, DC 20007, USA. ys82@georgetown.edu.
3
Department of Pharmacology and Physiology, Georgetown University Medical Center, Georgetown University, 3900 Reservoir Road NW, Washington, DC 20007, USA. ns1015@georgetown.edu.

Abstract

Pulmonary arterial hypertension (PAH) is a fatal disease without satisfactory therapeutic options. By the time patients are diagnosed with this disease, the remodeling of pulmonary arteries has already developed due to the abnormal growth of pulmonary vascular cells. Therefore, agents that reduce excess pulmonary vascular cells have therapeutic potential. Bcl-2 is known to function in an antioxidant pathway to prevent apoptosis. The present study examined the effects of inhibitors of the anti-apoptotic proteins Bcl-2 and Bcl-xL. ABT-263 (Navitoclax), ABT-199 (Venetoclax), ABT-737, and Obatoclax, which all promoted the death of cultured human pulmonary artery smooth muscle cells. Further examinations using ABT-263 showed that Bcl-2/Bcl-xL inhibition indeed promoted apoptotic programmed cell death. ABT-263-induced cell death was inhibited by antioxidants. ABT-263 also promoted autophagy; however, the inhibition of autophagy did not suppress ABT-263-induced cell death. This is in contrast to other previously studied drugs, including anthracyclines and proteasome inhibitors, which were found to mediate autophagy to induce cell death. The administration of ABT-263 to rats with PAH in vivo resulted in the reversal of pulmonary vascular remodeling. Thus, promoting apoptosis by inhibiting anti-apoptotic Bcl-2 and Bcl-xL effectively kills pulmonary vascular smooth muscle cells and reverses pulmonary vascular remodeling.

KEYWORDS:

Bcl-2; apoptosis; pulmonary hypertension; smooth muscle; vascular remodeling

PMID:
30373097
DOI:
10.3390/antiox7110150
Free full text

Supplemental Content

Full text links

Icon for Multidisciplinary Digital Publishing Institute (MDPI)
Loading ...
Support Center