Evidence for markers of hypoxia and apoptosis in explanted human carotid atherosclerotic plaques.

Abstract

Apoptosis and inflammation are important features of atherosclerotic plaques. We investigated whether a common signal molecule can trigger these two apparently separate pathways. Hypoxia inducible factor (HIF-1α) is known to participate in atherosclerosis and to stimulate apoptosis signal-regulating kinase 1 (ASK-1), one of the mitogen-activated protein kinases, which is activated by various extracellular stimuli and involved in a variety of cellular function. We tested carotid artery specimens from 50 subjects who underwent angioplasty and five age-matched controls for either Western blot or histologic analysis. The hypoxic status was investigated by means of HIF-1α expression in carotid specimens. HIF-1α was significantly upregulated in carotid specimens with respect to controls (P < .05), ASK-1 was detected in plaques of any composition from lipidic to calcific, and this expression increased with the stage of the plaque and with the expression of inflammatory (p-ERK, RANK-L, OPG) and apoptotic molecules (caspase 9, p-p-38, and p-JNK). Our data suggest that hypoxia is the key regulating factor that triggers inflammation as well as apoptosis in the human atherosclerotic plaque.