RESUMO
BACKGROUND: We investigated the potential contributions of tumor necrosis factor-alpha (TNF-alpha) on the incidence of acute myocardial rupture and subsequent chronic cardiac dysfunction after myocardial infarction (MI) in TNF knockout (TNF-/-) mice compared with C57/BL wild-type (WT) mice. METHODS AND RESULTS: Animals were randomized to left anterior descending ligation or sham operation and killed on days 3, 7, 14, and 28. We monitored cardiac rupture rate, cardiac function, inflammatory response, collagen degradation, and net collagen formation. We found the following: (1) within 1 week after MI, 53.3% (n=120) of WT mice died of cardiac rupture, in contrast to 2.5% (n=80) of TNF-/- mice; (2) inflammatory cell infiltration and cytokine expression were significantly higher in the infarct zone in WT than TNF-/- mice on day 3; (3) matrix metalloproteinase-9 and -2 activity in the infarcted myocardium was significantly higher in WT than in TNF-/- mice on day 3; (4) on day 28 after MI compared with sham, there was a significant decrease in LV developed pressure (74%) and +/-dP/dt(max) (68.3%/65.3%) in WT mice but a less significant decrease in +/-dP/dt(max) (25.8%/28.8%) in TNF-/- mice; (5) cardiac collagen volume fraction was lower in WT than in TNF-/- mice on days 3 and 7 but higher on day 28 compared with TNF-/- mice; and (6) a reduction in myocyte apoptosis in TNF-/- mice occurred on day 28 compared with WT mice. CONCLUSIONS: Elevated local TNF-alpha in the infarcted myocardium contributes to acute myocardial rupture and chronic left ventricle dysfunction by inducing exuberant local inflammatory response, matrix and collagen degradation, increased matrix metalloproteinase activity, and apoptosis.
Assuntos
Ruptura Cardíaca/etiologia , Infarto do Miocárdio/complicações , Miocárdio/química , Fator de Necrose Tumoral alfa/fisiologia , Disfunção Ventricular Esquerda/etiologia , Animais , Apoptose , Colágeno/análise , Colágeno/biossíntese , Colágeno/genética , Citocinas/biossíntese , Indução Enzimática , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Regulação da Expressão Gênica , Ruptura Cardíaca/genética , Ruptura Cardíaca/fisiopatologia , Metaloproteinase 2 da Matriz/biossíntese , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/biossíntese , Metaloproteinase 9 da Matriz/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocardite/patologia , Miocárdio/patologia , NF-kappa B/análise , Distribuição Aleatória , Fator de Transcrição RelA , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/deficiência , Fator de Necrose Tumoral alfa/genética , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/fisiopatologia , Remodelação VentricularRESUMO
BACKGROUND: Integrins are involved in structural remodeling and tissue repair. This study aimed to elucidate the role of the beta-integrins in cardiac remodeling after myocardial infarction (MI). METHODS AND RESULTS: The MI model was created by ligation of the left anterior descending coronary artery in rats. We detected cardiac integrins beta1 and beta3 gene expression (quantitative in situ hybridization) and protein production (Western blot and immunohistochemistry) and potential regulation by tumor necrosis factor (TNF) using neonatal ventricular myocytes and TNF-/- knockout mice. Integrins beta1 and beta3 gene expression and protein production were low in sham-operated hearts. After MI, the beta1 and beta3 mRNA and proteins were significantly increased at the site of MI at day 3, reached a peak at day 7, and gradually declined thereafter. Integrin beta1A localized primarily in fibroblasts and inflammatory cells, beta1D localized in myocytes, and integrin beta3 was associated primarily with endothelial and smooth muscle cells in peri-infarct vessels. In cultured myocytes, there was isoform transition from the adult beta1D to the fetal beta1A on exposure to TNF-alpha. This was confirmed in vivo in the peri-infarct myocytes, but the transition was voided in TNF-/--knockout mice. CONCLUSIONS: Integrins beta1 and beta3 are significantly activated in the infarcted myocardium. Integrin beta1 is active particularly at sites of inflammation and fibrosis, whereas integrin beta3 localizes to vessels in the peri-infarct zone in a temporally coordinated manner. Integrin beta1D to beta1A isoform transition in myocytes is regulated by TNF-alpha.
