Protein phosphatase type 2Cα and 2Cβ are involved in fatty acid-induced apoptosis of neuronal and endothelial cells

Abstract

Unsaturated fatty acids with special structural features have been shown to activate serine/threonine protein phosphatase type 2C (PP2C) isoforms alpha and beta at physiological Mg(2+)-concentrations in vitro. These compounds also induce apoptosis in neuronal and endothelial cells. In this study we further analysed this striking correlation and tried to elucidate whether or not there is a causative relationship between activation of PP2C and induction of apoptosis. We employed RNA interference to simultaneously knock down PP2Calpha and PP2Cbeta in SH-SY5Y cells or HUVECs, respectively. This downregulation was transient. Treatment of SH-SY5Y cells or HUVECs with oleic acid (18:1,cis-Delta(9)) caused apoptosis in a time- and concentration-dependent manner. In both cases, cells with reduced PP2C-levels were less susceptible to oleic acid-induced cell damage. In conclusion, our results demonstrate that PP2C activation by unsaturated fatty acids actually causes apoptosis in neuronal and endothelial cells.

Regulation of vascular endothelial cell barrier function and cytoskeleton structure by protein phosphatases of the PPP family

“…Western blot analysis and cloning work indicates that EC expresses all four major types of Ser/Thr phosphatases; moreover, a growing body of evidence points to their involvement in the regulation of endothelial barrier function (34,100,121,139,151,152,155).…”

A Functional, Genome-wide Evaluation of Liposensitive Yeast Identifies the “RE2 Required for Viability” (ARV1) Gene Product as a Major Component of Eukaryotic Fatty Acid Resistance

“…Saturated fatty acids (8 -11) and unsaturated fatty acids (UFA) (12)(13)(14)(15)(16)(17) induce cytotoxicity by different mechanisms but are normally accommodated in eukaryotic cells by esterification with alcohols to produce neutral lipids. Accordingly, DGAT1 Ϫ / Ϫ murine fibroblasts, deficient in a diacylglycerol acyltransferase encoding the committed terminal step in triglyceride biosynthesis, are highly sensitive to UFA and saturated fatty acid (18).…”

Unsaturated fatty acids liberated from VLDL cause apoptosis in endothelial cells

“…This protein can be dephosphorylated by PP2C a and b and other phosphatases [7] and is then able to induce apoptosis. Furthermore, we could show a causal relationship between PP2C activation by oleic acid and induction of apoptosis in endothelial cells via RNAi [13]. Finally, we were able to demonstrate that UFAs isolated from lipoproteins in vitro could activate PP2C and also caused apoptotic cell death in HUVECs [12].…”

“…On the other hand, we could significantly diminish apoptosis of HUVECs caused by oleic acid when PP2C was downregulated by the RNAi technique. The extent of apoptosis, however, was not completely abolished by PP2C knockdown suggesting that also other mechanisms of apoptotic damage might play a role [13].…”

“…Furthermore, we showed that isolated UFAs from lipoproteins, liberated by LPL in vitro, induced apoptosis in endothelial cells [12]. By means of RNAi technology we could demonstrate a causal relationship between activation of PP2C and induction of apoptosis in HUVECs [13].…”