Inhibition of Lp(a)-induced functional impairment of endothelial cells and endothelial progenitor cells by hepatocyte growth factor.
BACKGROUND
Lipoprotein (a) (Lp(a)) is one of the risk factors for peripheral artery disease (PAD). Our previous report demonstrated that hepatocyte growth factor (HGF) gene therapy attenuated the impairment of collateral formation in Lp(a) transgenic mice. Since risk factors for atherosclerosis accelerate endothelial senescence and impair angiogenesis, we examined the role of Lp(a) in dysfunction and senescence of endothelial progenitor cells (EPC) and endothelial cells.


METHODS
In vitro and in vivo incorporation assays were performed using ex-vivo expanded DiI-labeled human EPC. Senescence of cultured endothelial cells, production of oxidative stress and angiogenesis function were evaluated by SA-β-galactosidase staining, dihydroethidium (DHE) staining and Matrigel assay, respectively.


RESULTS
EPC transplantation significantly stimulated recovery of ischemic limb perfusion, while EPC pre-treated with Lp(a) did not increase ischemic limb perfusion. Impairment of angiogenesis by EPC with Lp(a) was associated with a significant decrease in CD31-positive capillaries and DiI-labeled EPC. Importantly, Lp(a) significantly accelerated the onset of senescence and production of reactive oxygen species (ROS) in human aortic endothelial cells, accompanied by a significant increase in the protein expression of p53 and p21. On the other hand, HGF significantly attenuated EPC dysfunction, senescence, ROS production, and p53 and p21 expression induced by Lp(a).


CONCLUSIONS
Lp(a) might affect atherosclerosis via acceleration of senescence, ROS production, and functional impairment of the endothelial cell lineage. HGF might have inhibitory effects on these atherogenic actions of Lp(a).
Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
Masaaki
M
Iwabayashi
Yoshiaki
Y
Taniyama
Fumihiro
F
Sanada
Junya
J
Azuma
Kazuma
K
Iekushi
Keita
K
Okayama
Amarnath
A
Chatterjee
Hiromi
H
Rakugi
Ryuichi
R
Morishita
D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism / Q000628:therapy; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D007511:Ischemia / Q000378:metabolism / Q000628:therapy; D017270:Lipoprotein(a) / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D018919:Neovascularization, Physiologic; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism
D017270:Lipoprotein(a); D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D017228:Hepatocyte Growth Factor