Deficiência da óxido nítrico sintase neuronal eleva mortalidade e acentua o remodelamento cardíaco após infarto do miocárdio: papel do equilíbrio entre o estresse nitrosativo e oxidativo

• Ano de defesa: 2006
• Autor(a) principal: Saraiva, Roberto Magalhães [UNIFESP]
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de São Paulo (UNIFESP)
• Palavras-chave em Português: Insuficiência Cardíaca Congestiva; Infarto do Miocárdio; Estresse Oxidativo; Óxido Nítrico; Camundongos
• Link de acesso: http://repositorio.unifesp.br/handle/11600/9293

Background: Neuronal nitric oxide synthase (NOS1) plays key cardiac physiologic roles, regulating excitation-contraction coupling and exerting an anti-oxidant effect that maintains tissue nitric oxide (NO)/redox equilibrium. We tested the hypothesis that NOS1 plays a protective effect post-myocardial infarction (MI). Methods: We studied mortality, cardiac remodeling, and upregulation of oxidative stress pathways following MI in NOS1 deficient (NOS1-/-) and wild-type C57BL6 (WT) mice. We constructed survival curves and studied the cardiac remodeling (echocardiography and histology), performance (echocardiography and hemodynamics), oxidative stress (oxidative fluorescence microtopography, xanthine oxidoreductase [XOR] and NADPH oxidase activities), NO production, and XOR, NADPH oxidase subunits and endothelial NOS (NOS3) expression. Results: Compared to WT, NOS1-/- mice had greater mortality (Hazard ratio 2.06, P = 0.036), and worse left ventricular fractional shortening (19.7 ± 1.5 vs 27.2 ± 1.5%, P<0.05), and cardiac remodeling with higher LV diastolic (5.5 ± 0.2 vs. 4.9 ± 0.1 mm, P<0.05) and systolic (4.4 ± 0.2 vs. 3.6 ± 0.1 mm, P<0.05) diameters, and more intense cardiac hypertrophy (residual cellular width = 14.9 ± 0.5 vs. 12.8 ± 0.5 μm, P<0.01) despite similar MI size. Superoxide production increased after MI in both NOS1-/- and WT animals, although NO increased only in WT. NADPH oxidase (P<0.05) activity and expression had similar and transient increases in both groups post MI. NOS1-/- mice had persistent basal and post-MI elevations in XOR activity, while WT mice presented transient increase in XOR activity post-MI. XOR expression increased transiently in both groups post-MI. NOS3 expression was upregulated post-MI in NOS1-/- mice. Conclusions: Together these findings support a protective role for intact NOS1 activity in the heart following MI. NOS1 deficiency contributes to an imbalance between oxidative stress and tissue NO signaling, providing a plausible mechanism for adverse consequences of NOS1 deficiency in states of myocardial injury.