Aldosterone Contributed to Pulmonary Arterial Hypertension Development via Stimulating Aquaporin Expression and Pulmonary Arterial Smooth Muscle Cells Proliferation

Abstract

Introduction and Objective: The regulatory network of aquaporin (AQP) 1 and renin-angiotensin-aldosterone (ALDO) system are not quite clear in pulmonary arterial hypertension (PAH). Thus, we explored the role of AQP1, ALDO and spirolactone (SP) in the PAH animal model and pulmonary arterial smooth muscle cells (PASMCs). Method: PAH rat model was established by monocrotaline (MCT) via intraperitoneal in SD rat. Hemodynamic measurement was conducted via the external jugular vein cannula. PASMCs were extracted from normal SD rat and cultured in SmGM medium. α-Actin expression was identified by immunocytochemistry. Protein levels were assessed by Western blot. Cell viability was assayed using the MTT method. Apoptosis rate was evaluated by flow cytometry. ALDO level was measured by ELISA. Result: SP decreased AQP1 and β-catenin expressions in PAH rat model induced successfully by MCT. Moreover, ALDO increased AQP1 expression and cell viability in PASMCs, which were extracted from rat and identified by α-actin expression. AQP1 downregulation decreased β-catenin expression, and SP lowered AQP1 and β-catenin expressions elevated by ALDO in PASMCs. SP offset ALDO's effect on the upregulation of cell viability as well as AQP1 and β-catenin expressions in PASMCs. In addition, AQP1 downregulation and SP have a negative effect on Ki-67 and proliferating cell nuclear antigen expressions as well as cell viability after ALDO treatment in PASMCs. Conclusion: ALDO might contribute to PAH development via stimulating AQP1 expression and PASMCs proliferation. However, SP could be considered an effective drug regulating PASMCs proliferation through modulating AQP1 and β-catenin expressions in PAH.

Aquaporins in lung health and disease: Emerging roles, regulation, and clinical implications

“…In this context, AQP1 deficiency (null mice) showed increase in lung ischemia-reperfusion injury that was mediated via lowered stability of HIF-2α [154]. In a recent study, increased AQP1 expression was shown to play a role in aldosterone mediated development of pulmonary arterial hypertension [155] In acute lung injury (ALI), pre-B cell colony-enhancing factor (PBEF), which is involved in enhancing the inflammatory factors, downregulated AQP1 expression primarily via MAPK pathways [156]. Another study using rat pleural mesothelial cells showed role of p38 MAPK pathway in downregulation of AQP1 by Staphylococcus peptidoglycan [157].…”

Monocrotaline-Induced Pulmonary Arterial Hypertension and Bosentan Treatment in Rats: Focus on Plasma and Erythrocyte Parameters

“…Aldosterone seems to contribute to monocrotaline-induced PAH development as its concentration was found to be increased in both plasma and lung homogenates, and spironolactone prevented pulmonary vascular remodeling [ 33 ]. Similar changes have been observed in human PAH [ 29 ].…”

Effects of mineralocorticoid receptor antagonists in heart failure with reduced ejection fraction patients with chronic obstructive pulmonary disease in EMPHASIS‐HF and RALES

“…COPD is itself a fluid‐retaining state associated with hyperaldosteronism 4,10–12 . The harmful effects of hyperaldosteronism in HFrEF are well recognised and aldosterone may also have detrimental effects in the pulmonary vasculature, which is especially relevant given the propensity of patients with COPD to develop pulmonary hypertension 13–17 …”

“…Each condition is associated with an increase in plasma aldosterone concentration and MRAs should help counter fluid retention, block any adverse effects of exogenous corticosteroids at the mineralocorticoid receptor and mitigate the risk of hypokalaemia with beta‐2 agonists 4,10–12 . In addition, MRAs seem to attenuate pathogenic vascular remodelling in the lungs, and right ventricular failure, in experimental models of pulmonary hypertension 13–17 . These problems also occur as secondary complications in some patients with COPD.…”

“…4,[10][11][12] In addition, MRAs seem to attenuate pathogenic vascular remodelling in the lungs, and right ventricular failure, in experimental models of pulmonary hypertension. [13][14][15][16][17] These problems also occur as secondary complications in some patients with COPD. Surprisingly, however, in a large Danish nationwide cohort, use of spironolactone in such patients was associated with a higher mortality than no use of spironolactone, the opposite of what was found for beta-blockers and renin-angiotensin system antagonists.…”