TRPC1 is regulated by caveolin-1 and is involved in oxidized  LDL-induced apoptosis of vascular smooth muscle cells.
Oxidized low-density lipoprotein (oxLDL) induced-apoptosis of vascular cells may participate in plaque instability and rupture. We have previously shown that vascular smooth muscle cells (VSMC) stably expressing caveolin-1 were more susceptible to oxLDL-induced apoptosis than VSMC expressing lower level of caveolin-1, and this was correlated with enhanced Ca(2+) entry and pro-apoptotic events. In this study, we aimed to identify the molecular events involved in oxLDL-induced Ca(2+) influx and their regulation by the structural protein caveolin-1. In VSMC, transient receptor potential canonical-1 (TRPC1) silencing by ARN interference prevents the Ca(2+) influx and reduces the toxicity induced by oxLDL. Moreover, caveolin-1 silencing induces concomitant decrease of TRPC1 expression and reduces oxLDL-induced apoptosis of VSMC. OxLDL enhanced the cell surface expression of TRPC1, as shown by biotinylation of cell surface proteins, and induced TRPC1 translocation into caveolar compartment, as assessed by subcellular fractionation. OxLDL-induced TRPC1 translocation was dependent on actin cytoskeleton and associated with a dramatic rise of 7-ketocholesterol (a major oxysterol in oxLDL) into caveolar membranes, whereas the caveolar content of cholesterol was unchanged. Altogether, the reported results show that TRPC1 channels play a role in Ca(2+) influx and Ca(2+) homeostasis deregulation that mediate apoptosis induced by oxLDL. These data also shed new light on the role of caveolin-1 and caveolar compartment as important regulators of TRPC1 trafficking to the plasma membrane and apoptotic processes that play a major role in atherosclerosis.
Ingueneau
Cécile
C
INSERM U858; Université de Toulouse; UPS, Institut de Médicine Moléculaire de Rangueil; Toulouse, France.
Huynh-Do
Uyen
U
University of Bern, Departement of Nephrology and Hypertension, and Department of Clinical Research, Inselpital, Switzerland.
Marcheix
Bertrand
B
INSERM U858; Université de Toulouse; UPS, Institut de Médicine Moléculaire de Rangueil; Toulouse, France.
Athias
Anne
A
Université de Bourgogne, Plateau Technique de Lipidomique - Dijon, France.
Gambert
Philippe
P
Université de Bourgogne, Plateau Technique de Lipidomique - Dijon, France.
Nègre-Salvayre
Anne
A
INSERM U858; Université de Toulouse; UPS, Institut de Médicine Moléculaire de Rangueil; Toulouse, France.
Salvayre
Robert
R
INSERM U858; Université de Toulouse; UPS, Institut de Médicine Moléculaire de Rangueil; Toulouse, France.
Vindis
Cécile
C
INSERM U858; Université de Toulouse; UPS, Institut de Médicine Moléculaire de Rangueil; Toulouse, France.
D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D051242:Caveolin 1 / Q000502:physiology*; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D008077:Lipoproteins, LDL / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D034741:RNA, Small Interfering; D050052:TRPC Cation Channels / Q000235:genetics*
C495540:CAV1 protein, human; D051242:Caveolin 1; D008077:Lipoproteins, LDL; D034741:RNA, Small Interfering; D050052:TRPC Cation Channels; C099252:oxidized low density lipoprotein; C096351:transient receptor potential cation channel, subfamily C, member 1