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.
Highlights
Pulmonary arterial hypertension (PAH) can affect males and females of any age, including children and young adults
To investigate the effects of Bcl-2/Bcl-xL inhibition on pulmonary vascular remodeling, Bcl-2/Bcl-xL inhibitors including ABT-263, ABT-199, ABT-737, and Obatoclax were studied in cultured human pulmonary artery smooth muscle cells (PASMCs)
All tested drugs that were dissolved in dimethyl sulfoxide (DMSO) at 1 μM significantly decreased the number of cells when compared to control cells treated with an equal amount of DMSO (Figure 1A)
Summary
Pulmonary arterial hypertension (PAH) can affect males and females of any age, including children and young adults. Despite the availability of approved drugs, PAH remains a fatal disease without a cure [1,2]. Major pathogenic features that increase pulmonary vascular resistance include the development of vascular remodeling, in which the pulmonary artery (PA) walls are thickened and the lumens are narrowed or occluded. Increased resistance puts strain on the right ventricle, and heart failure is the major cause of death among PAH patients [3,4]. Even with the currently available therapies, the prognosis remains poor; only 58–75% of patients survive for three years [7,8,9,10]. The currently available drugs primarily elicit vasorelaxation, and their ability to resolve pulmonary vascular remodeling is limited. PAH is a progressive disease, and by the time patients are diagnosed, pulmonary vascular remodeling has already occurred. Therapeutic strategies that reverse pulmonary vascular remodeling should have a significant impact on health by reducing the morbidity and mortality associated with this condition
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