RESUMO
Heart failure (HF) is characterized by abnormalities in beta-adrenergic receptor (betaAR) signaling, including an increase in betaAR kinase 1 (betaARK1) levels and activity. Gene therapy using a peptide inhibitor of betaARK1 (betaARKct) in infarcted rabbit hearts has improved compromised cardiac function. To determine whether betaARK1 inhibition improves survival in a mouse model of HF induced by myocardial infarction (MI), we studied wild-type (WT) and transgenic (TG) mice overexpressing betaARKct following MI. There was no difference in infarct size. Survival of WT mice with MI was 25% at 26 weeks. In contrast, 92% of betaARKct TG mice with MI survived (P = 0.01). betaARKct TG mice with MI at 8 weeks showed significantly higher fractional shortening compared with WT mice with MI (25.1 +/- 2.7% versus 14.2 +/- 1.0%; P < 0.05). Moreover, the biochemical betaAR abnormalities in WT mice with MI were prevented in betaARKct TG mice with MI. In conclusion, betaARK1 inhibition results in a marked increase in survival and improved cardiac function in a mouse model of HF induced by MI.
Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/prevenção & controle , Infarto do Miocárdio/mortalidade , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Estenose Coronária/fisiopatologia , Proteínas Quinases Dependentes de AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/uso terapêutico , Diástole/efeitos dos fármacos , Diástole/fisiologia , Modelos Animais de Doenças , Regulação para Baixo , Insuficiência Cardíaca/complicações , Ruptura Cardíaca Pós-Infarto/etiologia , Ruptura Cardíaca Pós-Infarto/mortalidade , Ruptura Cardíaca Pós-Infarto/fisiopatologia , Ruptura Cardíaca Pós-Infarto/prevenção & controle , Heterozigoto , Homozigoto , Hipertrofia Ventricular Esquerda/complicações , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos/genética , Infarto do Miocárdio/complicações , Infarto do Miocárdio/prevenção & controle , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Sístole/efeitos dos fármacos , Sístole/fisiologia , Quinases de Receptores Adrenérgicos betaRESUMO
Granulocyte-colony stimulating factor (G-CSF) has been reported to mobilize bone marrow multi-potent stem cells, which differentiate into cardiac myocytes after myocardial infarction (MI). However, there have not been any reports regarding the effect of G-CSF on stem cell infiltration in the MI site. Hearts of mice that had undergone coronary occlusion were isolated and digested with collagenase. Infiltrating cells in the heart were collected using Percoll density gradients. The infiltrating cells were sorted for side population (SP) cells using Hoechst 33342 dye. Hundreds of infiltrating SP cells were found in the heart from 1 to 14 d after MI. There were only a few SP cells in hearts without infarction. Infiltrating SP cells were increased in the 4-d G-CSF treated group compared with the vehicle group (1106 +/- 106 vs. 323 +/- 26/heart, P < 0.05). The infiltration of inflammatory cells was not influenced by the G-CSF treatment. In a separate series of experiments, we confirmed that the infiltrating SP cells were derived from bone marrow. That is, SP cells in the infarcted hearts of mice, which had been transplanted with bone marrow from ROSA 26 (beta-galactosidase transgenic) mice, were positive for beta-galactosidase. In the immunohistochemical examination, Sca-1(+)/CD45(-) cells were existed in the infarcted site after MI. Therefore, SP cells may infiltrate into infarcted heart. G-CSF augmented this kind of stem cell infiltration without increasing inflammatory cells. These results suggest that G-CSF may enhance myocardial regeneration without aggravated inflammation in the infarcted heart.
