Differential expression of genes in the calcium-signaling pathway underlies lesion development in the LDb mouse model of atherosclerosis

Mak, Solida; Sun, Hua; Acevedo, Frances; Shimmin, Lawrence C.; Zhao, Lei; Teng, Ba-Bie; Hixson, James E.

doi:10.1016/j.atherosclerosis.2010.06.038

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Volume 213, Issue 1 , Pages 40-51, November 2010

Differential expression of genes in the calcium-signaling pathway underlies lesion development in the LDb mouse model of atherosclerosis

Solida Mak
- The University of Texas Graduate School of Biomedical Science at Houston, Houston, TX 77030, USA
- Center for Human Genetics, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
- Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Hua Sun
- The University of Texas Graduate School of Biomedical Science at Houston, Houston, TX 77030, USA
- Center for Human Genetics, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Frances Acevedo
- Center for Human Genetics, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Lawrence C. Shimmin
- Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Lei Zhao
- Center for Human Genetics, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Ba-Bie Teng
- The University of Texas Graduate School of Biomedical Science at Houston, Houston, TX 77030, USA
- Center for Human Genetics, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
- Corresponding author at: Research Center for Human Genetics, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, 1825, Pressler St., Suite SRB 530D, Houston, TX, USA. Tel.: +1 713 500 2443; fax: +1 713 500 2447.
James E. Hixson
- The University of Texas Graduate School of Biomedical Science at Houston, Houston, TX 77030, USA
- Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
- Corresponding author at: Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA. Tel.: +1 713 500 9834; fax: +1 713 500 0900.

Received 12 December 2009; received in revised form 16 June 2010; accepted 23 June 2010. published online 28 July 2010.

Abstract

Objective

Atherosclerosis is influenced by the interaction of environmental and genetic susceptibility risk factors. We used global microarray expression profiling to investigate differentially regulated genes in aorta during development of atherosclerosis in a susceptible genetically modified mouse model in response to the interaction between risk factors including hyperlipidemic genotype, shear stress, diet, and age.

Methods and results

In this study we investigated transcriptional changes in lesion-prone and lesion-resistant regions of aortas in genetically modified mice lacking both genes of the LDL receptor and the apolipoprotein B mRNA editing enzyme (LDb; Ldlr^−/−Apobec1^−/−). Risk factors including hyperlipidemic genotype (LDb vs. C57BL/6 wildtype), shear stress (lesion-prone vs. lesion resistant aortic regions), diet (chow vs. Western high-fat), and age (2- vs. 8-months) were studied. We hybridized aortic RNA samples with microarray chips containing probes for 45,000 mouse genes and expressed sequence tags (ESTs). Overall, the differentially expressed genes were components of 20 metabolic and physiological pathways. Notably, calcium signaling is the major pathway identified with differential regulation of 30 genes within this pathway. We also found differential expression of calcium-signaling genes in cultured primary endothelial cells from lesion-prone and lesion-resistant arterial regions (LDb mice vs. C57BL/6 controls), providing further support for involvement of calcium signaling in the pathogenesis of atherosclerosis. Moreover, we demonstrated protein expression of genes in the calcium-signaling pathway using Western blot analysis and immunofluorescence.

Conclusions

Our results suggest that calcium signaling may play an important role in regulation of genes expressed in aorta during development of atherosclerosis. Calcium signaling may act via mechanistic responses to genetic, mechanical, and environmental insults that trigger an imbalance of intracellular calcium homeostasis, resulting in altered biological processes leading to lesion development.

Keywords: Atherosclerosis, cDNA microarray, Aorta, Risk factors, Calcium-signaling pathway