Faculty Collaboration Database

AMP kinase activation improves angiogenesis in pulmonary artery endothelial cells with in utero pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2013 Jan 01;304(1):L29-42

Date

10/30/2012

Pubmed ID

23103561

Pubmed Central ID

PMC3543642

DOI

10.1152/ajplung.00200.2012

Scopus ID

2-s2.0-84871870815 (requires institutional sign-in at Scopus site)   45 Citations

Abstract

Pulmonary artery endothelial cells (PAEC) isolated from fetal lambs with in utero pulmonary hypertension (IPH) have phenotypical changes that lead to increased reactive oxygen species (ROS) formation and impaired angiogenesis. AMP-activated protein kinase (AMPK) is known to be activated by ROS, which is expected to help angiogenesis in IPH-PAEC. The objectives of this study were to investigate AMPK responses in IPH and its role in angiogenesis. We observed that, compared with control PAEC, IPH-PAEC have decreased phosphorylation of AMPKα catalytic subunit and AMPK downstream enzymes, indicating a decrease in AMPK activity. In addition, the expression of AMPK kinases is decreased, and protein phosphatase 2 is increased in IPH-PAEC, potentially contributing to the decreased AMPK activation. Metformin, an AMPK activator, improved IPH-PAEC angiogenesis while increasing endothelial NO synthase (eNOS) serine(1179) phosphorylation and decreasing the eNOS-caveolin-1 association. Metformin also increased MnSOD activity and the expression of both eNOS and MnSOD. The increase in angiogenesis by Metformin is abolished by pretreatment with AMPK inhibitor, Compound C. Expression of vascular endothelial growth factor (VEGF) and platelet-derived growth factor β (PDGFβ) are decreased in IPH-PAEC compared with control PAEC and were not altered by Metformin. These data indicate that Metformin improves angiogenesis through mechanisms independent of these angiogenic factors. In conclusion, activation of AMPK restores angiogenesis and increases the bioavailability of nitric oxide in IPH. Whether Metformin is beneficial in the management of pulmonary hypertension requires further investigation.

Author List

Teng RJ, Du J, Afolayan AJ, Eis A, Shi Y, Konduri GG

Authors

Adeleye James Afolayan MD Associate Professor in the Pediatrics department at Medical College of Wisconsin
Girija Ganesh Konduri MD Chief, Professor in the Pediatrics department at Medical College of Wisconsin
Ru-Jeng Teng MD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

AMP-Activated Protein Kinases
Animals
Caveolin 1
Cells, Cultured
Endothelial Cells
Enzyme Activation
Hypertension, Pulmonary
Metformin
Neovascularization, Physiologic
Nitric Oxide Synthase Type III
Phosphorylation
Platelet-Derived Growth Factor
Pulmonary Artery
Pyrazoles
Pyrimidines
Reactive Oxygen Species
Sheep, Domestic
Superoxide Dismutase
Vascular Endothelial Growth Factor A