Absence of heme oxygenase‐1 exacerbates atherosclerotic lesion formation and vascular remodeling

Abstract

To examine the role of heme oxygenase (HO)-1 in the pathophysiology of vascular diseases, we generated mice deficient in both HO-1 and apolipoprotein E (HO-1-/-apoE-/-). Despite similar total plasma cholesterol levels in response to hypercholesterolemia, HO-1-/-apoE-/- mice, in comparison with HO-1+/+apoE-/- mice, had an accelerated and more advanced atherosclerotic lesion formation. In addition to greater lipid accumulation, these advanced lesions from HO-1-/-apoE-/- mice contained macrophages and smooth muscle alpha-actin-positive cells. We further tested the role of HO-1 on neointimal formation in a mouse model of vein graft stenosis. Autologous vein grafts in HO-1-/- mice showed robust neointima consisting of alpha-actin-positive vascular smooth muscle cells (VSMC) 10 days after surgery in comparison to the smaller neointima formed in autologous vein grafts in HO-1+/+ mice. However, at 14 days after surgery, the neointima from composite vessels of HO-1-/- mice was composed mainly of acellular material, indicative of substantial VSMC death. VSMC isolated from HO-1-/- mice were susceptible to oxidant stress, leading to cell death. Our data demonstrate that HO-1 plays an essential protective role in the pathophysiology of atherosclerosis and vein graft stenosis.

Neferine inhibits angiotensin II-stimulated proliferation in vascular smooth muscle cells through heme oxygenase-1

“…Data from previous studies suggested that induction of HO-1 could inhibit cell growth [12,22,23] . VSMCs from HO-1-deficient mice display enhanced DNA synthesis and cell growth [24] . Conversely, over-expression of HO-1 by either transfection of the HO-1 gene or exogenous administration of a certain HO-1 inducer reduces excessive VSMC proliferation [25] .…”

The Mononuclear Phagocyte System in Homeostasis and Disease: A Role for Heme Oxygenase-1

“…The general atheroprotective actions of HO-1 are well documented (114,190). Recently, a more complete understanding of this process has implicated HO-1 expression within MP as an effector of atheroprotection (128).…”

Bilirubin and Biliverdin Treatment of Atherosclerotic Diseases

“…11 The lack of HO-1 in HO-1 -/-/ApoE -/-double knock out mice dramatically worsens the process of atherogenesis. 12 It is generally assumed that Fe ++ , CO and/or biliverdin, the products of heme degradation, account for these anti-atherosclerotic effects even though the removal of heme by HO-1, and perhaps other effects of HO-1 may also be involved. Earlier studies from our laboratories showed that CO has anti-atherosclerotic effects by inhibition of VSMC proliferation.…”