关键词: 动脉粥样硬化； 易损斑块；  炎症； 血红素加氧酶

Abstract:

Objective     To explore the role of heme oxygenase-1(HO-1) in plaque progression and stabilization in atherosclerotic rabbits. Methods     After abdominal aortic balloon injury, 45 male New Zealand White rabbits were fed with an atherogenic diet for 24 weeks. From week 12 to week 24, animals were randomly divided into three groups, respectively receiving intraperitoneal injection of hemin to induce HO-1(hemin group), Sn-protoporphyrin IX (SnPP) to inhibit HO-1(SnPP group), and vehicle as controls. Vulnerable plaques were established by local transfection with the p53 gene, and challenged with injection of Russell′s viper venom and histamine to induce plaque rupture. Then all the rabbits were killed and their abdominal aortas were taken out to undergo pathological examination. Immunohistochemistry and real-time RT-PCR were performed to determine expressions of matrix metalloproteinase-9, interleukin-6 and tumor necrosis factor-α. Results    Hemin induced an increase in HO-1 mRNA, protein and enzyme activity in atherosclerotic plaques. This induction was correlated with a reduction in the progression of plaque size and modulations in morphological features and plaque composition toward increased stabilization, ie, thicker fibrous cap, more intra-plaque smooth muscle cells and collagen content, and less macrophages and lipid content. Additionally, expressions of inflammatory mediators, including matrix metalloproteinase-9, interleukin-6 and tumor necrosis factorα were also lowered by hemin treatment (all P<0.01). In contrast, SnPP treatment induced a reverse effect and augmented plaque progression and vulnerability. After pharmacological triggering, plaque rupture appeared in 5 rabbits in the control group(33%), 12 in the SnPP group (80%, P<0.05) and none in the hemin group (0%, P<0.05). Conclusion      HO-1 inhibits progression of advanced atherosclerotic plaques and promotes plaque stability, probably by modulating plaque composition and attenuating plaque inflammation.

Key words: Atherosclerosis;  Vulnerable plaque;  Inflammation;  Heme oxygenase