Mutation of delta-sarcoglycan is associated with Ca(2+) -dependent vascular remodeling in the Syrian hamster.
We examined whether mutation of the delta-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 Ca(2+)-handling proteins, and the presence of cyclin D1. In freshly isolated VSMCs from CHF 147 hamsters, voltage-independent basal Ca(2+) 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 delta-sarcoglycan gene increases plasma membrane permeability to Ca(2+), activates the Ca(2+)-regulated transcription factor NFAT, and leads to spontaneous mitochondrial aggregation, causing abnormal VSMC proliferation and apoptosis.
Lipskaia
Larissa
L
INSERM UMR S621, 91 bd de l'Hôpital, 75634 Paris Cedex 13, France.
Pinet
Caroline
C
Fromes
Yves
Y
Hatem
Stéphane
S
Cantaloube
Isabelle
I
Coulombe
Alain
A
Lompré
Anne-Marie
AM
D000818:Animals; D001013:Aorta, Thoracic; D017209:Apoptosis; D002118:Calcium / Q000037:antagonists & inhibitors; D015220:Calcium Channels / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D006224:Cricetinae; D016189:Dystrophin / Q000378:metabolism; D005260:Female; D008297:Male; D008647:Mesocricetus; D020748:Mibefradil / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D009154:Mutation; D050778:NFATC Transcription Factors / Q000378:metabolism; D049031:Sarcoglycans / Q000235:genetics / Q000502:physiology*
D015220:Calcium Channels; D016189:Dystrophin; D050778:NFATC Transcription Factors; D049031:Sarcoglycans; D020748:Mibefradil; D002118:Calcium