Expression of sterol regulatory element-binding transcription factor (SREBF) 2 and SREBF cleavage-activating protein (SCAP) in human atheroma and the association of their allelic variants with sudden cardiac death

Yue-Mei Fan,Jussi Mikkelsson,Terho Lehtimäki,Niku Oksala,Olli A Kajander,Janita Thusberg,Erkki Ilveskoski,Reijo Laaksonen,Juha-Pekka Salenius,Juhani T Soini,Mari Levula,Leena Kytömäki,Otso Järvinen,Pekka J Karhunen,Mauno Vihinen

doi:10.1186/1477-9560-6-17

Abstract

BackgroundDisturbed cellular cholesterol homeostasis may lead to accumulation of cholesterol in human atheroma plaques. Cellular cholesterol homeostasis is controlled by the sterol regulatory element-binding transcription factor 2 (SREBF-2) and the SREBF cleavage-activating protein (SCAP). We investigated whole genome expression in a series of human atherosclerotic samples from different vascular territories and studied whether the non-synonymous coding variants in the interacting domains of two genes, SREBF-2 1784G>C (rs2228314) and SCAP 2386A>G, are related to the progression of coronary atherosclerosis and the risk of pre-hospital sudden cardiac death (SCD).MethodsWhole genome expression profiling was completed in twenty vascular samples from carotid, aortic and femoral atherosclerotic plaques and six control samples from internal mammary arteries. Three hundred sudden pre-hospital deaths of middle-aged (33–69 years) Caucasian Finnish men were subjected to detailed autopsy in the Helsinki Sudden Death Study. Coronary narrowing and areas of coronary wall covered with fatty streaks or fibrotic, calcified or complicated lesions were measured and related to the SREBF-2 and SCAP genotypes.ResultsWhole genome expression profiling showed a significant (p = 0.02) down-regulation of SREBF-2 in atherosclerotic carotid plaques (types IV-V), but not in the aorta or femoral arteries (p = NS for both), as compared with the histologically confirmed non-atherosclerotic tissues. In logistic regression analysis, a significant interaction between the SREBF-2 1784G>C and the SCAP 2386A>G genotype was observed on the risk of SCD (p = 0.046). Men with the SREBF-2 C allele and the SCAP G allele had a significantly increased risk of SCD (OR 2.68, 95% CI 1.07–6.71), compared to SCAP AA homologous subjects carrying the SREBF-2 C allele. Furthermore, similar trends for having complicated lesions and for the occurrence of thrombosis were found, although the results were not statistically significant.ConclusionThe results suggest that the allelic variants (SREBF-2 1784G>C and SCAP 2386A>G) in the cholesterol homeostasis regulating SREBF-SCAP pathway may contribute to SCD in early middle-aged men.

Highlights

Disturbed cellular cholesterol homeostasis may lead to accumulation of cholesterol in human atheroma plaques
Cellular cholesterol homeostasis is controlled by sterol regulatory element-binding transcription factors (SREBFs), which are transcription factors that modulate the transcription of genes involved in lipid and cholesterol metabolism
The mutation position in sterol regulatory element-binding transcription factor 2 (SREBF-2) is not at all conserved, and the following amino acids are found at this position: Y, V, T, S, R, Q, L, K, G, E and A

Summary

Introduction

Disturbed cellular cholesterol homeostasis may lead to accumulation of cholesterol in human atheroma plaques. Cellular cholesterol homeostasis is controlled by the sterol regulatory element-binding transcription factor 2 (SREBF-2) and the SREBF cleavage-activating protein (SCAP). Cellular cholesterol homeostasis is controlled by sterol regulatory element-binding transcription factors (SREBFs), which are transcription factors that modulate the transcription of genes involved in lipid and cholesterol metabolism. In sterol-depleted cells, SREBF cleavage activating protein (SCAP) forms a complex with SREBF and assists in its transportation to the Golgi apparatus where it can be processed by two specific proteases and release the amino-terminal transcription-activation domain of the SREBF. The SREBFs consist of three different SREBF isoforms, SREBF-1a, SREBF-1c and SREBF-2 They are produced by two genes, with SREBF-1a and -1c transcribed from a single gene by alternative promoter use and splicing, and SREBF-2 from a separate gene [2]. There is considerable evidence suggesting that SREBF-2 is closely associated with cholesterol metabolism, while SREBF-1 is more associated with the control of genes involved in fatty acid metabolism [3,4]

Methods

Results

Conclusion