Abstract 11474: Hepatocyte Growth Factor Attenuates Lipoprotein(a) Induced Endothelial Lineage Cell Dysfunction
Background: Lipoprotein(a) (Lp(a)) is an independent risk factor for coronary artery disease (CAD) and peripheral artery disease (PAD). In contrast, hepatocyte growth factor (HGF) contributes to cell proliferation and angiogenesis, with multiple anti-oxidative and anti-inflammatory effects on various tissues and organs. Earlier we showed that HGF 1)rescues impaired collateral formation in Lp(a) transgenic mice (Circ. 2002), 2)attenuates anigiotensin II induced endothelial progenitor cell (EPC) senescence (Hypertens. 2009). In this study, we examine the effects of HGF on Lp(a) induced endothelial dysfunction.
Methods and Results: SA-β galactosidase staining was used to evaluate the senescence of human aortic endothelial cells (HAEC) and superoxide production was measured by dihydroethidium staining. A significant increase in the number of SA-β galactosidase positive cells was observed accompanied with accelerated superoxide production and the increased p53/p21 expression in Lp(a) treated HAECs (P<0.05). Continuous stimulation with Lp(a) for 72h significantly accelerated the collapse of tubular structure of HAECs on Matrigel (P<0.05). However, HGF significantly inhibited these actions (P<0.05). To confirm the function of EPCs, ex-vivo expanded DiI labeled human EPCs were co-cultured with HAECs on Matrigel. Lp(a) impaired the ability of EPCs to incorporate into tubular structures of HAECs significantly (Control:58%, Lp(a):31 % P<0.01). To further investigate the function of EPCs in ischemic tissue, EPCs were cultured according to the in vitro study protocol and transplanted into nude mouse hindlimb ischemia model. EPC transplantation was associated with a recovery of ischemic limb perfusion in EPC transplanted groups. Nevertheless, compared with other groups, mice receiving Lp(a)-treated EPC had severely impaired ischemic limb perfusion and markedly decreased numbers of DiI labeled EPCs and CD31 positive capillaries in ischemic tissue. These atherosclerotic actions of Lp(a) were markedly attenuated by administering HGF (P<0.05).
Conclusion: Lp(a) accelerates senescence and superoxide production in ECs and the functional impairment of EPCs. HGF might be suitable for the treatment of Lp(a)-induced endothelial dysfunction.
- © 2011 by American Heart Association, Inc.