Overexpression of heme oxygenase-1 in coronary atherosclerosis of Japanese autopsies with diabetes mellitus: Hisayama study

Abstract Few studies regarding the topographical expression of heme oxygenase-1 (HO-1) and its pathophysiological role in human coronary atherosclerotic lesions, particularly in relation to type 2 diabetes mellitus (DM) and intimal angiogenesis, have been reported. HO-1 expression was immunohistochemically examined in 312 tissue blocks of coronary arteries obtained from 53 Japanese autopsy cases in Hisayama cohort study that included 19 diabetic subjects and 34 age- and sex-matched non-diabetic subjects (56–93 years old, mean ± S.D.: 73 ± 10). The HO-1 was ubiquitously distributed in atherosclerotic intima, and was mainly expressed by macrophages and endothelial cells, and partly by smooth muscle cells. The prevalence of HO-1 expression increased as the lesion type (as classified by the American Heart Association (AHA) Committee) and stenotic grade progressed ( p < 0.0001), and was significantly higher in diabetic than in non-diabetic subjects ( p < 0.01). This HO-1 overexpression was associated with greater CD-68-positive macrophage infiltration ( p = 0.005). Interestingly, the distribution of HO-1-positive cells was accentuated in coronary atherosclerotic lesions with intimal microvessels in diabetic subjects ( p < 0.05), particularly those with hypercholesterolemia ( p < 0.05), and was preferentially distributed in the shoulder region of atherosclerotic lesion type IV in the AHA classification ( p < 0.01). In conclusion, HO-1 expression was distributed in overall human coronary atherosclerotic lesions, particularly in diabetic subjects, indicating that HO-1 expression is intimately associated with atherogenesis and may play an important role as an adaptive molecule in the inflammatory-repair process. The association of HO-1 overexpression with a greater extent of intraplaque angiogenesis suggests a multi-faceted role for HO-1 in modulating the progression of atherosclerosis.