title: Atorvastatin reduces long pentraxin 3 expression in vascular cells by inhibiting protein geranylgeranylation.
abstract: BACKGROUND
  The long pentraxin PTX3 is an acute-phase multi-functional protein that might play both positive and detrimental effects under different pathophysiological conditions. We previously showed that statins down-regulate the release of PTX3 in human endothelial cells (ECs). The present study investigated the mechanism mediating this effect, its occurrence in other cells involved in atherogenesis, and whether it takes place in experimental atherosclerosis.
  
  
  RESULTS
  We found that atorvastatin (1-5 μmol/L) decreased the production and release of PTX3 in human ECs through a post-transcriptional effect. Co-incubation with mevalonate or geranylgeranyl pyrophosphate prevented this effect. Direct blockade of geranylgeranyl transferase I by GGTI-286, treatment with the Rac inhibitor NSC23766 or silencing of the geranylgeranylated GTPase Rac2 by siRNA closely mimicked the action of atorvastatin. In contrast, inactivation of other geranylgeranylated proteins such as RhoA, RhoB, and RhoC or Rac1 did not affect PTX3 release. In addition, we found that atorvastatin also decreased PTX3 secretion in aortic SMCs through a mechanism likely dependent on protein geranylgeranylation, while no effect was observed in monocytes. Finally, we found that atherosclerotic lesions from cholesterol-fed rabbits treated with atorvastatin (2.5 mg/kg/day for 8 weeks) showed less immunoreactive PTX3 than lesions from control animals.
  
  
  CONCLUSIONS
  Results suggest that statins may interfere with PTX3 expression in vascular cells via inhibition of protein geranylgeranylation. Since PTX3 is increasingly regarded as an important mediator of the inflammatory response underlying atherosclerosis and its complications, these results highlight the need for further studies of the role of PTX3 and its potential pharmacological modulation in cardiovascular disease.
authors: Centro Cardiologico Monzino IRCCS, Via Parea 4, 20138 Milano, Italy.
authors: Roberta
authors: R
authors: Baetta
authors: Centro Cardiologico Monzino IRCCS, Via Parea 4, 20138 Milano, Italy.
authors: Sabrina
authors: S
authors: Lento
authors: Centro Cardiologico Monzino IRCCS, Via Parea 4, 20138 Milano, Italy.
authors: Stefania
authors: S
authors: Ghilardi
authors: Humanitas Clinical and Research Center, Via Manzoni 113, 20089 Rozzano, Milano, Italy.
authors: Elisa
authors: E
authors: Barbati
authors: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy; MultiMedica IRCCS, Via Milanese 300, 20099 Sesto San Giovanni, Milano, Italy.
authors: Alberto
authors: A
authors: Corsini
authors: Centro Cardiologico Monzino IRCCS, Via Parea 4, 20138 Milano, Italy; Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy.
authors: Elena
authors: E
authors: Tremoli
authors: Centro Cardiologico Monzino IRCCS, Via Parea 4, 20138 Milano, Italy. Electronic address: cristina.banfi@ccfm.it.
authors: Cristina
authors: C
authors: Banfi
mesh_terms: D000818:Animals; D000069059:Atorvastatin / Q000494:pharmacology*; D002097:C-Reactive Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D017368:Protein Prenylation / Q000187:drug effects / Q000502:physiology*; D011817:Rabbits; D000683:Serum Amyloid P-Component / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000099153:Pentraxins
chemical_list: D000069059:Atorvastatin; D002097:C-Reactive Protein; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000683:Serum Amyloid P-Component; D000099153:Pentraxins
keywords: Ammonium pyrrolidinedithiocarbamate (PubChem: CID 517348); Atherosclerosis; Atorvastatin (PubChem CID: 60822); Bay 11-7082 (PubChem CID: 5353431); FTI-276 (PubChem CID: 16760436); Farnesyl pyrophosphate (PubChem CID: 445713); Fluvastatin (PubChem CID: 23663976); GGTI-286 (PubChem CID: 3012117); Geranylgeranyl pyrophosphate (PubChem CID: 447277); HMG-CoA reductase inhibitors; Inflammation; NSC23766 (PubChem CID: 16759159); Pattern recognition proteins; ROCK inhibitor Y-27362 (PubChem CID: 9819206); Rac2