title: Selective homocysteine-lowering gene transfer attenuates pressure overload-induced cardiomyopathy via reduced oxidative stress.
abstract: Plasma homocysteine levels predict heart failure incidence in prospective epidemiological studies. We evaluated whether selective homocysteine-lowering gene transfer beneficially affects cardiac remodeling and function in a model of pressure overload-induced cardiomyopathy induced by transverse aortic constriction (TAC). Female C57BL/6 low-density lipoprotein receptor (Ldlr (-/-)) cystathionine-β-synthase (Cbs (+/-)) mice were fed standard chow (control mice) or a folate-depleted, methionine-enriched diet to induce hyperhomocysteinemia (diet mice). Three weeks after initiation of thisdiet, mice were intravenously injected with 5 × 10(10) viral particles of an E1E3E4-deleted hepatocyte-specific adenoviral vector expressing Cbs (AdCBS), with the same dose of control vector, or with saline buffer. TAC or sham operation was performed 2 weeks later. AdCBS gene transfer resulted in 86.4 % (p < 0.001) and 84.6 % (p < 0.001) lower homocysteine levels in diet sham mice and diet TAC mice, respectively. Mortality rate was significantly reduced in diet AdCBS TAC mice compared to diet TAC mice during a follow-up period of 8 weeks (hazard ratio for mortality 0.495, 95 % CI 0.249 to 0.985). Left ventricular hypertrophy (p < 0.01) and interstitial myocardial fibrosis (p < 0.001) were strikingly lower in control TAC mice and diet AdCBS TAC mice compared to diet TAC mice. Diastolic function in diet AdCBS TAC mice was similar to that of control TAC mice and was significantly improved compared to diet TACmice. AdCBS gene transfer potently reduced oxidative stress as evidenced by a reduction of plasma TBARS and a reduction of myocardial 3-nitrotyrosine-positive area (%). In conclusion, selective homocysteine lowering potently attenuates pressure overload-induced cardiomyopathy via reduced oxidative stress.
  
  
  CONCLUSIONS
  Plasma homocysteine levels predict heart failure incidence in epidemiological studies. Transverse aortic constriction (TAC) induces pressure overload. Selective homocysteine-lowering gene therapy reduces mortality after TAC. Selective homocysteine lowering attenuates cardiac hypertrophy and fibrosis after TAC. Decreased homocysteine levels enhance diastolic function and lower oxidative stress.
authors: Centre for Molecular and Vascular Biology, Department of Cardiovascular Sciences, Catholic University of Leuven, Campus Gasthuisberg, Herestraat 49 bus 911, 3000, Leuven, Belgium.
authors: Ilayaraja
authors: I
authors: Muthuramu
authors: Neha
authors: N
authors: Singh
authors: Ruhul
authors: R
authors: Amin
authors: Elena
authors: E
authors: Nefyodova
authors: Mirjam
authors: M
authors: Debasse
authors: Isa
authors: I
authors: Van Horenbeeck
authors: Frank
authors: F
authors: Jacobs
authors: Bart
authors: B
authors: De Geest
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000150:complications / Q000235:genetics / Q000473:pathology / Q000628:therapy; D009202:Cardiomyopathies / Q000097:blood / Q000150:complications / Q000235:genetics* / Q000628:therapy*; D003541:Cystathionine beta-Synthase / Q000235:genetics*; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006439:Hemodynamics; D006710:Homocysteine / Q000097:blood* / Q000235:genetics; D020138:Hyperhomocysteinemia / Q000097:blood / Q000150:complications / Q000235:genetics* / Q000628:therapy*; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000473:pathology; D018384:Oxidative Stress
chemical_list: D006710:Homocysteine; D003541:Cystathionine beta-Synthase