Abstract
To explore the role of FoxO1 and apoptosis in a rat model of chronic thromboembolic pulmonary hypertension (CTEPH). Rats were randomly divided into a sham group (n = 45) and an experimental group (n = 45). Autologous blood clots were injected into rats three times to induce CTEPH. Rats were further divided into three subgroups: a 1-week subgroup (n = 15), a 2-week subgroup (n = 15), and a 4-week subgroup (n = 15). Mean pulmonary arterial pressure (mPAP) and histopathology were evaluated at each time point. FoxO1, Bad, and Bcl-2 levels were examined at each time point using reverse transcription PCR and western blotting. The mPAP and vessel wall area/total area (WA/TA) ratio in the experimental group gradually increased in a time-dependent manner (P < 0.05). Both the mRNA and protein levels of FoxO1 decreased in the CTEPH rats compared to in the sham group. In addition, embolization led to the up-regulation of Bad and the down-regulation of Bcl-2 (P < 0.05). FoxO1 and apoptosis play an important role in the pathogenesis of CTEPH. Apoptosis-resistant pulmonary artery endothelial cells may play an important role in remodeling of the rat pulmonary artery.
Highlights
Chronic thromboembolic pulmonary hypertension (CTEPH) is a subtype of pulmonary hypertension (PH)[1]
Apoptosis and vascular remolding in chronic thromboembolic pulmonary hypertension (CTEPH)
Inflammation induced by a pulmonary embolism enhances the interaction between pulmonary arterial endothelial cell (PAEC) injury and thrombosis, further aggravating the vascular injury and promoting remolding; the latter is characterized by intimal thickening, increased pulmonary vascular resistance, and pulmonary hypertension[13]
Summary
Chronic thromboembolic pulmonary hypertension (CTEPH) is a subtype of pulmonary hypertension (PH) (group 4)[1]. The risk factors for CTEPH include recurrent pulmonary embolism, large thrombi, and young age[4, 5] Both pulmonary arterial endothelial cell (PAEC) and thrombosis lead to pulmonary vascular endothelial hyperplasia, thickening of the middle layer, and blood vessel occlusion[6,7,8], the underlying mechanisms behind these processes have not been elucidated. Another study showed that increased proliferation of apoptosis-resistant PAECs occurs in idiopathic pulmonary hypertension[11]; these PAECs present had elevated factor VIII and Bcl-XL levels[12, 13]. It is unclear whether these changes occur in the vascular remolding process during the transition from pulmonary embolism to CTEPH. We speculate that FoxO1 may play a direct role in PAEC apoptosis in CTEPH
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