BACKGROUND: Increasing evidences indicate that an activated renin-angiotensin system (RAS) causes an imbalance between the vasoconstrictive and vasodilator mechanisms involving the pulmonary circulation leading to the development of pulmonary arterial hypertension (PAH). Angiotensin-converting enzyme 2 (ACE2), a primary component of the vasoprotective axis in RAS, is recently identified that it has regulatory actions in lung pathophysiology, but the mechanism in these processes is uncertain yet. METHODS: Severe PAH was induced by monocrotaline injection one week following pneumonectomy in rats. The activation of ACE2 by continuous injection of resorcinolnaphthalein was studied by real time-polymerase chain reaction (RT-PCR), Western blotting and fluorogenic peptide assay. Endothelial functions were evaluated by the response to acetylcholine and cytokines were measured by RT-PCR seven days after monocrotaline injection. The PAH-related hemodynamics and pathological changes were examined at day 21 when severe PAH was completely established. RESULTS: Resorcinolnaphthalein caused significant activation of ACE2 in both normal and diseased rats in 7 days after treatment. The pulmonary arterial pressure (PAP) started to increase at least 7 days after monocrotaline injection, and the rats developed severe PAH in 21 days with high PAP, right ventricular hypertrophy and neointimal formation. Treatment with resorcinolnaphthalein prevented these features. Resorcinolnaphthalein caused an improved endothelia-dependent vasorelaxation and decrease in proinflammatory cytokines (tumor necrosis factor (TNF)-α, monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-6) and increase in anti-inflammatory cytokine IL-10 in the early stage of the pathogenesis. CONCLUSIONS: These results demonstrated that activation of ACE2 by continuous injection of resorcinolnaphthalein prevented the development of PAH through improving early endothelial dysfunction and mediating the level of proinflammatory and anti-inflammatory cytokines.
BACKGROUND: Increasing evidences indicate that an activated renin-angiotensin system (RAS) causes an imbalance between the vasoconstrictive and vasodilator mechanisms involving the pulmonary circulation leading to the development of pulmonary arterial hypertension (PAH). Angiotensin-converting enzyme 2 (ACE2), a primary component of the vasoprotective axis in RAS, is recently identified that it has regulatory actions in lung pathophysiology, but the mechanism in these processes is uncertain yet. METHODS: Severe PAH was induced by monocrotaline injection one week following pneumonectomy in rats. The activation of ACE2 by continuous injection of resorcinolnaphthalein was studied by real time-polymerase chain reaction (RT-PCR), Western blotting and fluorogenic peptide assay. Endothelial functions were evaluated by the response to acetylcholine and cytokines were measured by RT-PCR seven days after monocrotaline injection. The PAH-related hemodynamics and pathological changes were examined at day 21 when severe PAH was completely established. RESULTS:Resorcinolnaphthalein caused significant activation of ACE2 in both normal and diseased rats in 7 days after treatment. The pulmonary arterial pressure (PAP) started to increase at least 7 days after monocrotaline injection, and the rats developed severe PAH in 21 days with high PAP, right ventricular hypertrophy and neointimal formation. Treatment with resorcinolnaphthalein prevented these features. Resorcinolnaphthalein caused an improved endothelia-dependent vasorelaxation and decrease in proinflammatory cytokines (tumor necrosis factor (TNF)-α, monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-6) and increase in anti-inflammatory cytokine IL-10 in the early stage of the pathogenesis. CONCLUSIONS: These results demonstrated that activation of ACE2 by continuous injection of resorcinolnaphthalein prevented the development of PAH through improving early endothelial dysfunction and mediating the level of proinflammatory and anti-inflammatory cytokines.
Authors: Yang Zhang; Jian Liu; Jiang-Yun Luo; Xiao Yu Tian; Wai San Cheang; Jian Xu; Chi Wai Lau; Li Wang; Wing Tak Wong; Chi Ming Wong; Hui Yao Lan; Xiaoqiang Yao; Mohan K Raizada; Yu Huang Journal: Antioxid Redox Signal Date: 2015-05-14 Impact factor: 8.401
Authors: Michael J Coles; Muaaz Masood; Madeline M Crowley; Amit Hudgi; Chijioke Okereke; Jeremy Klein Journal: Dig Dis Sci Date: 2022-03-30 Impact factor: 3.487