Published online before print May 3, 2007

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(American Journal of Pathology. 2007;171:162-171.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.070054

Mutation of -Sarcoglycan Is Associated with Ca²⁺-Dependent Vascular Remodeling in the Syrian Hamster

Larissa Lipskaia^*, Caroline Pinet^*, Yves Fromes, Stéphane Hatem^*, Isabelle Cantaloube^*, Alain Coulombe^* and Anne-Marie Lompré^*

From INSERM U621, Université Pierre et Marie Curie-Paris6, Unité Mixte de Recherche (UMR) S621,^* Paris; and INSERM U582, Institut de Myologie, Université Pierre et Marie Curie-Paris6, UMR S582, Groupe Hospitalier Paris Saint Joseph, Servicede Chirurgie Cardiaque, Paris, France

We examined whether mutation of the -sarcoglycan gene, which causes dilated cardiomyopathy, also alters the vascular smooth muscle cell (VSMC) phenotype and arterial function in the Syrian hamster CHF 147. Thoracic aorta media thickness showed marked variability in diseased hamsters with zones of atrophy and hypertrophied segments. CHF-147 VSMCs displayed a proliferating/"synthetic" phenotype characterized by the absence of the smooth muscle myosin heavy chain SM2, dystrophin, and Ca²⁺-handling proteins, and the presence of cyclin D1. In freshly isolated VSMCs from CHF 147 hamsters, voltage-independent basal Ca²⁺ channels showed enhanced activity similar to that in proliferating wild-type (WT) cells. The transcription factor NFAT (nuclear factor of activated T cells) was spontaneously active in freshly isolated CHF 147 VSMCs, as in proliferating VSMCs from WT hamsters. Mibefradil inhibited B-type channels, NFAT activity, and VSMC proliferation. CHF 147 hamsters had abundant apoptotic cells distributed in patches along the aorta, and clusters of inactive mitochondria were observed in 25% of isolated CHF 147 cells, whereas no such clusters were seen in WT cells. In conclusion, mutation of the -sarcoglycan gene increases plasma membrane permeability to Ca²⁺, activates the Ca²⁺-regulated transcription factor NFAT, and leads to spontaneous mitochondrial aggregation, causing abnormal VSMC proliferation and apoptosis.

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