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

• Published in: Journal of vascular surgery Vol. 52; no. 4; pp. 1015 - 1021
• Main Authors: Bitto, Alessandra, De Caridi, Giovanni, Polito, Francesca, Calò, Margherita, Irrera, Natasha, Altavilla, Domenica, Spinelli, Francesco, Squadrito, Francesco
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.10.2010; Elsevier
• Subjects: Angioplasty; Apoptosis; Biological and medical sciences; Biomarkers - analysis; Blotting, Western; Carotid Arteries - chemistry; Carotid Arteries - pathology; Carotid Artery Diseases - metabolism; Carotid Artery Diseases - pathology; Carotid Artery Diseases - therapy; Case-Control Studies; Caspase 9 - analysis; Cell Hypoxia; Extracellular Signal-Regulated MAP Kinases - analysis; Finland; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - analysis; Immunohistochemistry; Inflammation Mediators - analysis; JNK Mitogen-Activated Protein Kinases - analysis; MAP Kinase Kinase Kinase 5 - analysis; Medical sciences; Neurology; Nitric Oxide Synthase Type II - analysis; Nitric Oxide Synthase Type III - analysis; Osteoprotegerin - analysis; p38 Mitogen-Activated Protein Kinases - analysis; Phosphorylation; RANK Ligand - metabolism; Surgery; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Up-Regulation; Vascular diseases and vascular malformations of the nervous system; Vascular surgery: aorta, extremities, vena cava. Surgery of the lymphatic vessels; Finland; Vascular disease; Human; Oxygen; Atherosclerotic plaque; Carotid; Surgery; Atherosclerosis; Explant; Hypoxia; Cardiovascular disease; Apoptosis
• ISSN: 0741-5214; 1097-6809; 1097-6809
• DOI: 10.1016/j.jvs.2010.05.116

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. This study adds evidence that HIF-1α is important in the oxidative stress response in the developing atherosclerotic plaque as it modulates both inflammatory and mitochondrion-related apoptotic pathways. Future therapy targeting HIF-1α may limit atherosclerosis development.