Critical role for lactate dehydrogenase A in aerobic glycolysis that sustains pulmonary microvascular endothelial cell proliferation

American Journal of Physiology - Lung Cellular and Molecular Physiology - Tập 299 Số 4 - Trang L513-L522 - 2010
Glenda Parra‐Bonilla1,2, Diego F. Alvarez1,3,2, Abu‐Bakr Al‐Mehdi1,2, Mikhail Alexeyev1,4, Troy Stevens1,3,2
1Center for Lung Biology, University of South Alabama, Mobile, Alabama
2Department of Pharmacology
3Department of Medicine
4Department of Cell Biology and Neuroscience, and

Tóm tắt

Pulmonary microvascular endothelial cells possess both highly proliferative and angiogenic capacities, yet it is unclear how these cells sustain the metabolic requirements essential for such growth. Rapidly proliferating cells rely on aerobic glycolysis to sustain growth, which is characterized by glucose consumption, glucose fermentation to lactate, and lactic acidosis, all in the presence of sufficient oxygen concentrations. Lactate dehydrogenase A converts pyruvate to lactate necessary to sustain rapid flux through glycolysis. We therefore tested the hypothesis that pulmonary microvascular endothelial cells express lactate dehydrogenase A necessary to utilize aerobic glycolysis and support their growth. Pulmonary microvascular endothelial cell (PMVEC) growth curves were conducted over a 7-day period. PMVECs consumed glucose, converted glucose into lactate, and acidified the media. Restricting extracellular glucose abolished the lactic acidosis and reduced PMVEC growth, as did replacing glucose with galactose. In contrast, slow-growing pulmonary artery endothelial cells (PAECs) minimally consumed glucose and did not develop a lactic acidosis throughout the growth curve. Oxygen consumption was twofold higher in PAECs than in PMVECs, yet total cellular ATP concentrations were twofold higher in PMVECs. Glucose transporter 1, hexokinase-2, and lactate dehydrogenase A were all upregulated in PMVECs compared with their macrovascular counterparts. Inhibiting lactate dehydrogenase A activity and expression prevented lactic acidosis and reduced PMVEC growth. Thus PMVECs utilize aerobic glycolysis to sustain their rapid growth rates, which is dependent on lactate dehydrogenase A.

Từ khóa


Tài liệu tham khảo

10.1007/978-0-387-69945-5_7

10.1007/s11033-009-9647-7

10.1152/ajplung.00314.2007

10.1096/fj.03-1001fje

10.1096/fasebj.11.5.9141507

10.1152/ajplung.00316.2007

10.1073/pnas.96.4.1559

10.1152/ajplung.00083.2002

10.1002/jps.10389

10.1016/j.ccr.2006.04.023

10.1530/rep.0.1210181

10.1016/j.mvr.2004.02.002

Greiner EF, 1994, J Biol Chem, 269, 31484, 10.1016/S0021-9258(18)31720-4

10.1111/j.1432-1033.1993.tb17637.x

10.1042/bj3430281

10.1016/j.cell.2008.08.021

10.1152/physrev.1992.72.2.369

10.1042/bj1740703

10.1016/j.mvr.2003.11.006

Merezhinskaya N, 2009, Histol Histopathol, 24, 243

Mothersill C, 2000, Br J Cancer, 82, 1740, 10.1054/bjoc.2000.1109

10.1016/0014-4827(59)90069-2

10.1055/s-0030-1253452

10.1242/jeb.01961

10.1073/pnas.88.24.11081

10.1073/pnas.0601026103

10.1126/science.1174665

10.2527/1998.7661671x

10.1016/j.ymben.2009.08.001

10.1152/ajplung.00304.2006

10.1378/chest.128.6_suppl.558S

10.1152/ajplung.1999.277.1.L119

10.3109/10623329509024653

10.1111/j.1365-2362.1987.tb01236.x

10.1046/j.1524-475X.2003.11621.x

10.1126/science.1160809

10.1016/j.mito.2009.09.006

10.1038/261702a0

Warburg O, 1956, Science, 124, 269, 10.1126/science.124.3215.269

10.1126/science.123.3191.309

10.1210/me.2008-0179

10.1126/science.1164097

10.1073/pnas.0605080104

Thông tin
Thông tin xuất bản

American Journal of Physiology - Lung Cellular and Molecular Physiology

Tập 299 Số 4

L513-L522

Thông tin tác giả