The Pleiotropic Effects of Atorvastatin on Stable Angina Patients: Evidence by Analysis of High-Density Lipoprotein Size and Subclasses, and Plasma mRNA

Summary Background: High-density lipoproteins (HDL) have atheroprotective biological properties: antioxidative, anti-apoptotic, anti-inflammatory, and they have the efflux capacity of cellular cholesterol. Plasma mRNA analysis can be used to investigate statin pleiotropy in vivo as a new analytical tool for non-invasive assessment of gene expression in vascular beds. The aim of this study was to assess the pleiotropic effects of atorvastatin in stable angina patients with highrisk values (group A) as compared with patients who had borderline and desirable HDL-cholesterol (HDL-C) values (group B). Methods: The atorvastatin therapy (20 mg/day) was given to forty-three patients with stable angina for 10 weeks. We investigated three statin pleiotropy-targeted genes: intercellular adhesion molecule-1, chemokine (C-C motif) ligand 2 and cathepsin S and assessed by gel electrophoresis gradient the effects of atorvastatin on HDL size and subclasses. Results: In group A, after therapy, HDL-C concentration was significantly increased but not in group B. Atorvastatin lowered plasma chemokine (C-C motif) ligand 2 and intercellular adhesion molecule-1 mRNA levels in both groups, but did not change the plasma cathepsin S mRNA levels. In group A only, baseline total bilirubin showed negative cor relations with the genes of cathepsin S (r=-0.506; p=0.023) and significantly increased after therapy. Conclusion: HDL-C and bilirubin can be promising therapeutic targets in the treatment of cardiovascular diseases. Analysis of cell-free mRNA in plasma might become a useful tool for estimating statin pleiotropy Kratak sodržaj Uvod: Lipoproteini velike gustine (HDL) imaju ateroprotektivne biološke osobine: antioksidativne, antiapoptotičke, antiinflamatorne kao i kapacitet da izvlače holesterol iz ćelija. Analiza plazmatske mRNA može da se koristi za ispitivanje plejotropnih efekata statina in vivo kao novo analitičko sredstvo za neinvazivnu procenu ekspresije gena u zidu krvnog suda. Cilj ove studije je bio da se procene plejotropni efekti atorvastatina kod pacijenata sa stabilnom anginom sa visokorizičnim vrednostima (grupa A) u odnosu na pacijente sa graničnim i poželjnim vrednostima HDL holesterola (HDL- C) (grupa B). Metode: Četrdesettri pacijenta sa stabilnom anginom su primala terapiju atorvastatinom (20 mg/dan) 10 nedelja. Mi smo ispitivali tri gena značajna za plejotropno delovanje statina: intracelularni adhezioni molekul-1, hemokin (C-C motiv) ligand 2 i katepsin S i procenjivali smo efekte atorvastatina na veliCinu i raspodelu HDL subfrakcija promoću elektroforeze na poliakrilamidnom gradijent gelu. Rezuttati: U grupi A, posle terapije, HDL-C koncentracija se značajno povećala, ali ne i u grupi B. Atoivastatin je snizio plazmatski nivo hemokin (C-C motiv) liganda 2 i intracelularnog adhezionog molekula-1 mRNA u obe grupe, ali nije promenio plazmatski nivo gena za katepsin S. Samo u grupi A, ukupni bilirubin je pokazao negativnu korelaciju sa genom za katepsin S (r=-0,506; p=0,023) pre zapotinjanja terapije i značajni porast nakon terapije atorvastatinom. Zaključak: HDL-C i bilirubin mogu biti obećavajući terapijski ciljevi u lečenju kardiovaskularnih bolesti. Analiza slobodne mRNA (eng. cell-free mRNA) u plazmi može postati korisno sredstvo za procenu plejotropnog delovanja statina