Role of Cholesterol and Membrane Lipid Rafts in SPC-Induced Ca2+-Sensitization Leading to Vasospasm

In arterial strips of patients with normal serum cholesterol levels, SPC-induced Ca2+-sensitization of VSM contraction was not observed. In contrast, SPC significantly enhanced contraction of VSM in hypercholesterolemic patients (Morikage et al., 2006). This result indicated that cholesterol may be involved in SPC- induced Ca2+-sensitization of VSM contraction. Cholesterol, a lipid molecule, is an essential structural component in the cell membrane. Much evidence demonstrated that serum cholesterol levels are strongly related to the occurrence of the cardiovascular events (Nelson, 2013; Peters et al., 2016; Unni et al., 2016). SPC-induced contraction was well correlated with the amount of total and LDL-cholesterol. This contraction showed a negative correlation with the amount of HDL-cholesterol (Morikage et al., 2006). In arterial strips of rabbits, the similar results that SPC-induced contraction was correlated with the levels of cholesterol in the serum were obtained. In rabbits, SPC-induced VSM contraction decreased upon oral administration of EPA or pravastatin, cholesterol-lowering agent. In addition, SPC-induced contraction was significantly decreased in the vascular strips which were deleted cholesterol with b-cyclodextrin (b-CD) (Morikage et al., 2006). Recently, we found that SPC-induced contraction was also correlated with the levels of cholesterol in the vascular smooth muscle tissue. In the range of 13.72-40.66 gg cholesterol/10 mg tissue, SPC-induced contraction was correlated with the amount of cholesterol in the tissue (unpublished data).

Although the relationship between cholesterol levels and Ca2+-sensitization of VSM contraction has been clarified, the mechanism by which cholesterol enhances Ca2+-sensitization of VSM contraction are not fully elucidated. Membrane lipid rafts are microdomains enriched in certain glycosphingolipids, gangliosides, and cholesterol (Rog and Vattulainen, 2014; Simons and Ikonen, 1997). They contain more cholesterol than other non-raft membranes in smooth muscle. The treatment with b-CD decreased not only cholesterol but also caveolin-1, a marker of lipid rafts, indicating that b-CD selectively disrupted the structure of cholesterol-enriched membrane microdomains, i.e., membrane lipid rafts. Membrane lipid rafts contain more cholesterol and recruits many signaling molecules (Head et al., 2014). In smooth muscle cells, we found that SPC induced the translocation of Fyn and ROK to the membrane lipid rafts using immunofluorescence staining and confocal microscopy (Morikage et al., 2006; Nakao et al., 2002). The treatment with b-CD inhibited this translocation of Fyn and ROK (unpublished data). These results suggested that membrane lipid rafts serving as a scaffold for recruiting Fyn and ROK play a vital role in SPC-induced Ca2+- sensitization of VSM contraction (Fig. 13.1).

Signaling pathway of SPC-induced Ca+-sensitization and the roles of cholesterol and membrane lipid rafts in SPC- induced Ca-sensitization leading to vasospasm

Figure 13.1 Signaling pathway of SPC-induced Ca2+-sensitization and the roles of cholesterol and membrane lipid rafts in SPC- induced Ca2+-sensitization leading to vasospasm.

< Prev   CONTENTS   Source   Next >