Glenn Foundation for Medical Research, Inc.

High-density lipoprotein (HDL) is known for its cardioprotective properties independent from its cholesterol transport activity. These properties are mediated by activation of kinases such as protein kinase C (PKC). Connexin43 (Cx43) is a gap junction protein present in ventricular cardiomyocytes. PKC-dependent phosphorylation modifies Cx43 gap junction channel properties and is involved in cardioprotection. We hypothesized that cardioprotective properties of HDL may be mediated in part by affecting Cx43 gap junction channels.

Neonatal rat cardiomyocytes were treated with HDL and Cx43 phosphorylation was evaluated by western blotting and immunofluorescence. We found that HDL promoted phosphorylation of Cx43 with a maximal induction at 5 min, which was inhibited by pre-treatment with various PKC inhibitors. Sphingosine-1-phosphate (S1P), a component of HDL, induced effects that were similar to those of HDL. These compounds significantly reduced diffusion of fluorescent dye among cardiomyocytes (∼50%) which could be prevented by PKC inhibition. As observed during optical recordings of transmembrane voltage, HDL and S1P depressed impulse conduction only minimally (<5%). Moreover, 5 min of HDL and S1P treatment at the onset of reperfusion significantly reduced infarct size (∼50%) in response to 30 min ischaemia in ex vivo experiments.

Short-term treatment with HDL or S1P induces phosphorylation of Cx43 by a PKC-dependent pathway. HDL-induced phosphorylation of Cx43 reduced the diffusion of large tracer molecules between cells, whereas impulse conduction was maintained. Moreover, 5 min treatment with HDL confers cardioprotection against ischaemia/reperfusion injury. These results link Cx43 for the first time to the short-term cardioprotective effects of HDL.

A polemic in response to the work of Kuipers and van den Elsen (ibid, p365-366) who showed that simvastatin does not downregulate MHC2TA and HLA-DRA promoter transcription and who further suggested that the immunomodulatory effects of statins is caused not by the inhibition of MHC2TA transcription but disruption of lipid rafts.

Statins have long been thought to exert their benefits by reducing cholesterol synthesis. However, the fact that mevalonate is the precursor of isoprenoids that regulate diverse cellular functions has led investigators to examine pleiotropic effects for these agents. Major histocompatibility complex class II (MHC-II) molecules, which affect the immune response and organ rejection after transplantation, may be induced by the proinflammatory cytokine interferon gamma (IFN-gamma). An experiment was conducted to determine whether statins affect the regulation of MHC-II expression by IFN-gamma in cultured human endothelial cells and monocyte/macrophages. Statins were found to repress the induction of MHC-II by IFN-gamma. This may explain the immunosuppressive effects of statins seen in two clinical trials of organ transplantation and suggest a potential role for statins as immunosuppressive agents.