Heme oxygenase-1 ameliorates oxidative stress-induced endothelial senescence via regulating endothelial nitric oxide synthase activation and coupling.

AIM: Premature senescence of vascular endothelial cells is a leading cause of various cardiovascular diseases. Therapies targeting endothelial senescence would have important clinical implications. The present study was aimed to evaluate the potential of heme oxygenase-1 (HO-1) as a therapeutic target for endothelial senescence.

METHODS AND RESULTS: Upregulation of HO-1 by Hemin or adenovirus infection reversed H2 O2 -induced senescence in human umbilical vein endothelial cells (HUVECs); whereas depletion of HO-1 by siRNA or HO-1 inhibitor protoporphyrin IX zinc (II) (ZnPP) triggered HUVEC senescence. Mechanistically, overexpression of HO-1 enhanced the interaction between HO-1 and endothelial nitric oxide synthase (eNOS), and promoted the interaction between eNOS and its upstream kinase Akt, thus resulting in an enhancement of eNOS phosphorylation at Ser1177 and a subsequent increase of nitric oxide (NO) production. Moreover, HO-1 induction prevented the decrease of eNOS dimer/monomer ratio stimulated by H2 O2 via its antioxidant properties. Contrarily, HO-1 silencing impaired eNOS phosphorylation and accelerated eNOS uncoupling. In vivo , Hemin treatment alleviated senescence of endothelial cells of the aorta from spontaneously hypertensive rats, through upregulating eNOS phosphorylation at Ser1177.

CONCLUSIONS: HO-1 ameliorated endothelial senescence through enhancing eNOS activation and defending eNOS uncoupling, suggesting that HO-1 is a potential target for treating endothelial senescence.