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


METHODS
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.


RESULTS
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).


CONCLUSIONS
Our data suggest that hypoxia is the key regulating factor that triggers inflammation as well as apoptosis in the human atherosclerotic plaque.
Bitto
Alessandra
A
Department of Clinical and Experimental Medicine and Vascular Surgery, Section of Pharmacology, School of Medicine, Messina, Italy.
De Caridi
Giovanni
G
Polito
Francesca
F
Calò
Margherita
M
Irrera
Natasha
N
Altavilla
Domenica
D
Spinelli
Francesco
F
Squadrito
Francesco
F
D017130:Angioplasty; D017209:Apoptosis; D015415:Biomarkers / Q000032:analysis; D015153:Blotting, Western; D002339:Carotid Arteries / Q000737:chemistry* / Q000473:pathology; D002340:Carotid Artery Diseases / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D016022:Case-Control Studies; D053453:Caspase 9 / Q000032:analysis; D015687:Cell Hypoxia; D048049:Extracellular Signal-Regulated MAP Kinases / Q000032:analysis; D005387:Finland; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis*; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000032:analysis; D048031:JNK Mitogen-Activated Protein Kinases / Q000032:analysis; D048848:MAP Kinase Kinase Kinase 5 / Q000032:analysis*; D052247:Nitric Oxide Synthase Type II / Q000032:analysis; D052250:Nitric Oxide Synthase Type III / Q000032:analysis; D053244:Osteoprotegerin / Q000032:analysis; D010766:Phosphorylation; D053245:RANK Ligand / Q000378:metabolism; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000032:analysis
D015415:Biomarkers; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018836:Inflammation Mediators; D053244:Osteoprotegerin; D053245:RANK Ligand; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; C496319:NOS2 protein, human; C496314:NOS3 protein, human; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; C506433:CASP9 protein, human; D053453:Caspase 9