title: 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.affiliation: Protein Chemistry Unit, Institute of Biomedicine/Anatomy, University of Helsinki, Helsinki, Finland. saara.ihalainen@helsinki.fi
authors.forename: Saara
authors.initials: S
authors.lastname: Ihalainen
authors.forename: Rabah
authors.initials: R
authors.lastname: Soliymani
authors.forename: Erika
authors.initials: E
authors.lastname: Iivanainen
authors.forename: Kati
authors.initials: K
authors.lastname: Mykkänen
authors.forename: Annele
authors.initials: A
authors.lastname: Sainio
authors.forename: Minna
authors.initials: M
authors.lastname: Pöyhönen
authors.forename: Klaus
authors.initials: K
authors.lastname: Elenius
authors.forename: Hannu
authors.initials: H
authors.lastname: Järveläinen
authors.forename: Matti
authors.initials: M
authors.lastname: Viitanen
authors.forename: Hannu
authors.initials: H
authors.lastname: Kalimo
authors.forename: Marc
authors.initials: M
authors.lastname: Baumann
mesh_terms: D046589:CADASIL / Q000473:pathology*; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D015180:Electrophoresis, Gel, Two-Dimensional; D005782:Gels; D020869:Gene Expression Profiling; D006801:Humans; D007231:Infant, Newborn; D009119:Muscle Contraction; D009131:Muscle, Smooth, Vascular / Q000737:chemistry* / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000737:chemistry* / Q000473:pathology*; D011506:Proteins / Q000378:metabolism; D020543:Proteome / Q000032:analysis*
chemical_list: D005782:Gels; D011506:Proteins; D020543:Proteome; D003094:Collagen