title: Protective effects of statin on cardiac fibrosis and apoptosis in adrenomedullin-knockout mice treated with angiotensin II and high salt loading.
abstract: Statins exert pleiotropic effects, including antioxidative and cellular protective effects. Endogenous adrenomedullin (AM) induces anti-inflammatory, anti-fibrotic and proangiogenic effects. We examined the effects of simvastatin on cardiac fibrosis and apoptosis in AM heterozygous knockout (AM(+/-)) mice treated with angiotensin (Ang) II and high salt loading. Seven-week-old AM(+/-) mice were infused with Ang II while on a high-salt diet with or without simvastatin for 2 weeks. Hearts were stained by hematoxylin-eosin or Masson's trichrome, and were immunostained with isolectin B(4) and α-smooth muscle actin antibodies. Expression of c-Kit and Sca-1 messenger RNA (mRNA) was evaluated by real-time PCR analysis. Apoptotic cells in hearts were identified by terminal deoxynucleotidyl transferase-mediated UTP end labeling (TUNEL) staining. Hearts from Ang II/salt loading AM(+/-) mice showed marked perivascular fibrosis around coronary arteries. Treatment with simvastatin significantly inhibited the fibrosis around coronary arteries in Ang II/salt-loading AM(+/-) mice. Expression of c-Kit and Sca-1 mRNAs in hearts from Ang II/salt-loading AM(+/-) mice was significantly lower than in hearts from wild-type mice. Treatment with simvastatin significantly increased the suppressed expression of c-Kit and Sca-1 mRNAs. In addition, treatment with simvastatin significantly increased the number of isolectin B(4)-positive capillary arteries in hearts from Ang II/salt-loading AM(+/-) mice. Ang II/high salt significantly increased apoptotic cells in hearts from AM(+/-) mice; this trend was reversed by treatment with simvastatin. Thus, statins have potent cardioprotective effects that may be associated with anti-fibrotic, proangiogenic and anti-apoptotic effects in Ang II/salt-loading AM(+/-) mice.
authors.affiliation: Division of Life Science, Advanced Research Institute for the Sciences and Humanities, Nihon University Graduate School, Tokyo, Japan.
authors.forename: Chii
authors.initials: C
authors.lastname: Yamamoto
authors.forename: Noboru
authors.initials: N
authors.lastname: Fukuda
authors.forename: Medet
authors.initials: M
authors.lastname: Jumabay
authors.forename: Kosuke
authors.initials: K
authors.lastname: Saito
authors.forename: Taro
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ueno
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Soma
authors.forename: Koichi
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Shimosawa
mesh_terms: D000199:Actins / Q000378:metabolism; D053607:Adrenomedullin / Q000235:genetics*; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D002196:Capillaries / Q000378:metabolism / Q000473:pathology; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D006023:Glycoproteins / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D019821:Simvastatin / Q000627:therapeutic use*; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D000199:Actins; D000950:Antigens, Ly; D006023:Glycoproteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D017673:Sodium Chloride, Dietary; C544013:alpha-smooth muscle actin, mouse; C473590:isolectin B4-binding glycoprotein, mouse; D000804:Angiotensin II; D053607:Adrenomedullin; D019821:Simvastatin; D019009:Proto-Oncogene Proteins c-kit