Proteome analysis of cultivated vascular smooth muscle cells from a CADASIL patient.

Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a vascular dementing disease caused by mutations in the NOTCH3 gene, most which are missense mutations leading to an uneven number of cysteine residues in epidermal growth factor-like repeats in the extracellular domain of Notch3 receptor (N3ECD). CADASIL is characterized by degeneration of vascular smooth muscle cells (VSMC) and accumulation of N3ECD on the VSMCs of small and middle-sized arteries. Recent studies have demonstrated that impairment of Notch3 signaling is not the primary cause of the disease. In the present study we used proteomic analysis to characterize the protein expression pattern of a unique material of genetically genuine cultured human CADASIL VSMCs. We identified 11 differentially expressed proteins, which are involved in protein degradation and folding, contraction of VSMCs, and cellular stress. Our findings indicate that misfolding of Notch3 may cause endoplasmic reticulum stress and activation of unfolded protein response, leading to increased reactive oxygen species and inhibition of cell proliferation. In addition, upregulation of contractile proteins suggests an alteration in the signaling system of VSMC contraction. The accumulation of N3ECD on the cell surface possibly upregulates the angiotensin II regulatory feedback loop and thereby enhances the readiness of the cells to respond to angiotensin II stimulation.

• Authors: Saara Ihalainen, Rabah Soliymani, Erika Iivanainen, Kati Mykkänen, Annele Sainio, Minna Pöyhönen, Klaus Elenius, Hannu Järveläinen, Matti Viitanen, Hannu Kalimo, Marc Baumann
• Journal: Molecular medicine (Cambridge, Mass.) (Mol Med) 2007 May-Jun Vol. 13 Issue 5-6 Pg. 305-14 ISSN: 1076-1551 [Print] England
• PMID: 17622327 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Gels
• Proteins
• Proteome
• Collagen

Topics

• CADASIL (pathology)
• Cells, Cultured
• Collagen (metabolism)
• Electrophoresis, Gel, Two-Dimensional
• Gels
• Gene Expression Profiling
• Humans
• Infant, Newborn
• Muscle Contraction
• Muscle, Smooth, Vascular (chemistry, pathology)
• Myocytes, Smooth Muscle (chemistry, pathology)
• Proteins (metabolism)
• Proteome (analysis)