Overexpression Of Heme Oxygenase-1 In Human Coronary Atherosclerosis With DiabetesMellitus

Background: Heme oxygenase (HO) is the initial and rate-limiting enzyme in the oxidativedegradation of heme to equimolar quantities of biliverdin, an antioxidant rapidly convertedto bilirubin via the enzyme biliverdin reductase, and carbon monoxide (CO), an antiapoptoticvasodilator, and free iron that is promptly sequestered into ferritin. Inducible hemeoxygenase-1 (HO-1) is overexpressed in inflammatory processe, providing not only tissueprotection by suppressive effect on oxidative stressed but also promotion of tissue repair viaVEGF-related angiogenesis. Atherosclerosis is promoted by multifactorial oxidative stressesinduced by hyperlipidemia, hypertension, diabetes mellitus (DM) smoking and others, andhas been thought to be an angiogenesis-related chronic inflammation. To my knowledge, theexpression of HO-1 and its pathophygiological role have not bee previously reported inhuman coronary atherosclerotic lesions with DM.Subjects and Methods, and Results: HO-1 expression was immunohistochemicallyexamined in coronary atherosclerosis of autopsied patients with DM and non-diabetesmellitus (NDM), using 312 tissue blocks of coronary arteries obtained from Japanese 53cases (56～93 years old, mean±SD: 73±10). The HO-1 was ubiquitously and largelyexpressed by macrophages, and endothelial cells (ECs) of both coronary arteries and imtimalnewly formed vessels, and partly smooth muscle cells (SMCs) in atherosclerotic intima. Theprevalence of HO-1 expression increased as the atherosclerotic lesion type and stenotic gradeprogressed, and was significantly higher in DM than NDM (P＜0.001). HO-1 expression in DM group was furthermore enhanced with advanced iesions and smoking. Interestingly, thedistribution of HO-1-positive cells was accentuated in coronary atherosclerotic lesions withnewly formed blood vessels in DM group and preferentially distributed in the shoulderregion and fibrous cap of atherosclerotic lesion typeⅣof AHA classification.Conclusion: Immunohistochemical HO-1 expression was distributed in overall humancoronary atherosclerotic lesions particularly in DM, and accompanied positive correlationwith intimal neovascularization in coronary atherosclerotic lesions, indicating that HO-1function is intimately integrated in the development and progression of atherosclerosis underinflammatory-repair process induced by redox stresses in DM.