Physiological cyclic strain promotes endothelial cell survival via the induction of heme oxygenase-1

Abstract

Endothelial cells (ECs) are constantly subjected to cyclic strain that arises from periodic change in vessel wall diameter as a result of pulsatile blood flow. Application of physiological levels of cyclic strain inhibits EC apoptosis; however, the underlying mechanism is not known. Since heme oxygenase-1 (HO-1) is a potent inhibitor of apoptosis, the present study investigated whether HO-1 contributes to the antiapoptotic action of cyclic strain. Administration of physiological cyclic strain (6% at 1 Hz) to human aortic ECs stimulated an increase in HO-1 activity, protein, and mRNA expression. The induction of HO-1 was preceded by a rise in reactive oxygen species (ROS) and Nrf2 protein expression. Cyclic strain also stimulated an increase in HO-1 promoter activity that was prevented by mutating the antioxidant responsive element in the promoter or by overexpressing dominant-negative Nrf2. In addition, the strain-mediated induction of HO-1 and activation of Nrf2 was abolished by the antioxidant N-acetyl-l-cysteine. Finally, application of cyclic strain blocked inflammatory cytokine-mediated EC death and apoptosis. However, the protective action of cyclic strain was reversed by the HO inhibitor tin protoporphyrin-IX and was absent in ECs isolated from HO-1-deficient mice. In conclusion, the present study demonstrates that a hemodynamically relevant level of cyclic strain stimulates HO-1 gene expression in ECs via the ROS-Nrf2 signaling pathway to inhibit EC death. The ability of cyclic strain to induce HO-1 expression may provide an important mechanism by which hemodynamic forces promote EC survival and vascular homeostasis.

Heme Oxygenase in Neonatal Lung Injury and Repair

“…In vitro, transfection with the human HO-1 gene increased blood vessel formation (24). In endothelial cells, hemodynamically relevant cyclic strain stimulated HO-1 gene expression and inhibited cell death (63). In vivo, lentiviral vectors with microRNA sequences controlled by vascular endothelium cadherin were used to study the role of lung endothelial HO-1 in mice exposed to hyperoxia (119).…”

Nicorandil Inhibits Cyclic Strain-Induced Interleukin-8 Expression in Human Umbilical Vein Endothelial Cells

“…Moreover, HO-1 overexpression reduces the production of ROS and attenuates the production of inflammatory cytokines, including IL-8, by activating ECs and macrophages [39,40] . Furthermore, the induction of HO-1 expression in ECs restores the endothelial integrity of injured vessels by stimulating the proliferation and migration of ECs from regions adjacent to the injured artery and by recruiting circulating endothelial progenitor cells to the site of damage [41] . Several therapeutic agents, including statins, resveratrol, rapamycin, paclitaxel, NO, aspirin, and probucol, induce HO-1 expression [32,42] .…”

“…In addition, HO-1 silencing significantly abrogated the inhibitory effects of nicorandil on cyclic strain-induced IL-8 expression, suggesting that the anti-inflammatory action of nicorandil may, at least partly, be attributed to nicorandil-induced HO-1 expression as a defense mechanism. Liu et al [41] found that cyclic strain significantly inhibits cytokine-mediated EC apoptosis, and that HO-1 expression underlies this cytoprotective effect. Nevertheless, further investigation is necessary to fully characterize the association between HO-1 and IL-8 expression.…”

Regulation of the HMOX1 gene by the transcription factor AP-2δ with unique DNA binding site

“…Therefore, its significance is notably wider than only haem elimination. HMOX1 is one of the most highly induced genes in cells exposed to stressful conditions, and hundreds of experiments have demonstrated that the products of HMOX1 activity are involved in the maintenance of cell homoeostasis (29). The importance of HMOX1 in cardiovascular diseases and cancer progression has been commonly accepted, particularly when considering the variability of HMOX1 in the human population, resulting from HMOX1 promoter polymorphism (30).…”