title: Raloxifene attenuates Gas6 and apoptosis in experimental aortic valve disease in renal failure.
abstract: Renal failure is associated with aortic valve calcification. Using our rat model of uremia-induced reversible aortic valve calcification, we assessed the role of apoptosis and survival pathways in that disease. We also explored the effects of raloxifene, an estrogen receptor modulator, on valvular calcification. Gene array analysis was performed in aortic valves obtained from three groups of rats (n = 7 rats/group): calcified valves obtained from rats fed with uremic diet, valves after calcification resolution following diet cessation, and control. In addition, four groups of rats (n = 10 rats/group) were used to evaluate the effect of raloxifene in aortic valve calcification: three groups as mentioned above and a fourth group fed with the uremic diet that also received daily raloxifene. Evaluation included imaging, histology, and antigen expression analysis. Gene array results showed that the majority of the altered expressed genes were in diet group valves. Most apoptosis-related genes were changed in a proapoptotic direction in calcified valves. Apoptosis and decreases in several survival pathways were confirmed in calcified valves. Resolution of aortic valve calcification was accompanied by decreased apoptosis and upregulation of survival pathways. Imaging and histology demonstrated that raloxifene significantly decreased aortic valve calcification. In conclusion, downregulation of several survival pathways and apoptosis are involved in the pathogenesis of aortic valve calcification. The beneficial effect of raloxifene in valve calcification is related to apoptosis modulation. This novel observation is important for developing remedies for aortic valve calcification in patients with renal failure.
authors.affiliation: Cardiovascular Research Center, Hadassah-Hebrew Univ. Medical Center, Jerusalem 91120, Israel. monysh@gmail.com
authors.forename: Mony
authors.initials: M
authors.lastname: Shuvy
authors.forename: Suzan
authors.initials: S
authors.lastname: Abedat
authors.forename: Ronen
authors.initials: R
authors.lastname: Beeri
authors.forename: Michael
authors.initials: M
authors.lastname: Valitsky
authors.forename: Sameh
authors.initials: S
authors.lastname: Daher
authors.forename: Miriam
authors.initials: M
authors.lastname: Kott-Gutkowski
authors.forename: Anca
authors.initials: A
authors.lastname: Gal-Moscovici
authors.forename: Jacob
authors.initials: J
authors.lastname: Sosna
authors.forename: Nalini M
authors.initials: NM
authors.lastname: Rajamannan
authors.forename: Chaim
authors.initials: C
authors.lastname: Lotan
mesh_terms: D000818:Animals; D001021:Aortic Valve / Q000378:metabolism* / Q000473:pathology*; D017209:Apoptosis / Q000187:drug effects*; D002114:Calcinosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006349:Heart Valve Diseases / Q000378:metabolism* / Q000473:pathology* / Q000517:prevention & control; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020849:Raloxifene Hydrochloride / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D051437:Renal Insufficiency / Q000150:complications*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction; D014511:Uremia / Q000150:complications; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D020929:Mitogen-Activated Protein Kinase Kinases; D051057:Proto-Oncogene Proteins c-akt; D020849:Raloxifene Hydrochloride; D020845:Selective Estrogen Receptor Modulators; D000099255:Growth Arrest-Specific Protein 6