Dietary Geranylgeranyl Pyrophosphate Counteracts the Benefits of Statin Therapy in Experimental Pulmonary Hypertension

Background: The mevalonate pathway generates endogenous cholesterol and intermediates including geranylgeranyl pyrophosphate (GGPP). By reducing GGPP production, statins exert pleiotropic or cholesterol-independent effects. potential regulation of homeostasis through dietary intake the interaction with concomitant statin therapy is unknown. Methods: We developed a sensitive high-pressure liquid chromatography technique to quantify conducted proteomics, qualitative real-time polymerase chain reaction screening, Western blot determine signaling cascades, gene expression, protein–protein interaction, protein membrane trafficking in wild-type transgenic rats. Results: contents were highly variable depending on food source that differentially regulated blood levels Diets containing intermediate high reduced abolished effects rats hypoxia- monocrotaline-induced pulmonary hypertension: this was rescuable by methyl-allylthiosulfinate methyl-allylthiosulfinate–rich garlic extracts. In human artery smooth muscle cells treated statins, hypoxia activated RhoA an extracellular GGPP-dependent manner. Hypoxia-induced ROCK2 (Rho associated coiled-coil kinase 2)/Rab10 (Ras-related rab-10) prevented recovered exogenous GGPP. hypoxia-activated RhoA/ROCK2 rat upregulated expression Ca 2+ -sensing receptor (CaSR) HIMF (hypoxia-induced mitogenic factor), mechanism attenuated treatment regained Rab10 knockdown almost abrogated hypoxia-promoted CaSR trafficking, process diminished resumed hypertension mutated at binding motif between efficiency abolished. humans fed diet, increased. This statin-lowering plasma GGPP, also hypoxia-enhanced activity monocytes rescued Conclusions: There important interferes experimental hypertension. These observations rely key central role RhoA-ROCK2 cascade activation Rab10-faciliated subsequent overexpression CaSR. findings warrant clinical investigation for perhaps other diseases combining garlic-derived extracts thus circumventing variations.