Protective Roles of Endothelial AMP-Activated Protein Kinase Against Hypoxia-Induced Pulmonary Hypertension in Mice

Abstract

C ytokines/chemokines and growth factors regulate pulmonary endothelial function and influence the development of pulmonary arterial hypertension (PAH).1 PAH is characterized by pulmonary vascular remodeling and perivascular inflammation, leading to right ventricular (RV) failure and premature death. [2][3][4][5] Endothelial dysfunction is a crucial pathogenic status that triggers a variety of vascular disorders, such as PAH. 6,7 Endothelial dysfunction is also considered a key underlying feature in most forms of clinical and experimental PAH, which is enhanced by inflammatory cytokines/ chemokines and growth factors.1,8 Indeed, we experience rapid progression and worsening of PAH, especially when complicated with infectious diseases, such as pneumonia and catheter-related infection.8 Pulmonary endothelial dysfunction in patients with PAH enhances pulmonary vascular remodeling through impaired release of vasodilators, such as nitric oxide (NO) and prostacyclin. [9][10][11] AMP-activated protein kinase (AMPK) is a heterotrimeric complex consisting of a catalytic subunit α and 2 regulatory subunits β and γ, and it is expressed in various tissues and Molecular Medicine© 2016 American Heart Association, Inc. ). In contrast, development of hypoxia-induced PH was accelerated in eAMPK -/-mice compared with controls. Furthermore, the exacerbation of PH in eAMPK -/-mice was accompanied by reduced endothelial function, upregulation of growth factors, and increased proliferation of pulmonary artery smooth muscle cells. Importantly, conditioned medium from endothelial cells promoted pulmonary artery smooth muscle cell proliferation, which was further enhanced by the treatment with AMPK inhibitor. Serum levels of inflammatory cytokines, including tumor necrosis factor-α and interferon-γ were significantly increased in patients with PAH compared with healthy controls. Consistently, endothelial AMPK and cell proliferation were significantly reduced by the treatment with serum from patients with PAH compared with controls. Importantly, long-term treatment with metformin, an AMPK activator, significantly attenuated hypoxiainduced PH in mice. Conclusions:

AMPKα2 Regulates Hypoxia-Inducible Factor-1α Stability and Neutrophil Survival to Promote Vascular Repair After Ischemia

“…Indeed, AMPK activation by oral administration of metformin has been shown to inhibit pulmonary VSMC proliferation and ameliorate the development of pulmonary hypertension. 1 The pathobiology of cardiovascular diseases includes endothelial dysfunction, Figure. Roles of AMP-activated protein kinase (AMPK)-α1 and AMPK-α2 in endothelial cells, vascular smooth muscle cells (VSMCs), and inflammatory cells. The RhoA (Ras homolog gene family member A)/Rho-kinase system is activated by many mechanisms, including signals from cytokines/chemokines and growth factors, leading to agonist-induced VSMC contraction.…”

“…irculating cytokines/chemokines and growth factors regulate endothelial function 1 and influence the development of cardiovascular diseases. 2 Cardiovascular diseases are characterized by endothelial dysfunction, 3 vascular smooth muscle cell (VSMC) proliferation, 4 and inflammatory cell migration, leading to obliteration or excessive enlargement of vascular lumens.…”

“…10 Endothelial-specific AMPK-knockout mice and the resultant endothelial dysfunction induce increased expression of inflammatory cell adhesion molecules. 1 Accumulated inflammatory cells generate an oxidizing environment, which involves abundant reactive oxygen species, inflammatory cytokines/chemokines, and growth factors that contribute to aortic aneurysm formation, 11 which is also regulated by AMPK-α2 in VSMCs. 12 Oxidative stress and a shift in the cellular redox balance have been linked with endothelial dysfunction at the early stages of cardiovascular diseases.…”

Development of Novel Therapies for Cardiovascular Diseases by Clinical Application of Basic Research

“…Pulmonary artery ECs are important for pulmonary vascular homeostasis whereas EC dysfunction accelerates the development of PH. 15,43, 46 As a degree research project, I demonstrated the protective roles of the endogenous erythropoietin (Epo)/Epo receptor (EpoR) system in endothelial function and homeostasis. 21 Additionally, EpoR −/− -rescued mice revealed a crucial role of the endogenous Epo/EpoR system in the ischemic heart 22 and ischemia-induced angiogenesis.…”

“…59-61 imaging techniques to evaluate pulmonary arterial remodeling in patients with PAH have been developed, 62, 63 and, in addition, it has been found that pravastatin and metformin ameliorate hypoxia-induced PH in mice. 25, 46 Recently, microarray analyses using PAHPASMCs to identify further common pathogenic proteins showed significant changes in 1,858 genes in PAH-PASMCs compared with control PASMCs. Some novel targets to develop therapeutic agents for patients with PAH were identified (Figure 2).…”