RESUMO
An inflammatory response is required for tissue healing after a myocardial infarction (MI), but the process must be balanced to prevent maladaptive remodeling. This study shows that improved survival and cardiac function following MI, in mice deficient for the NLRP3 inflammasome, can be recapitulated in wild-type mice receiving bone marrow from Nlrp3 -/- mice. This suggests that NLRP3 activation in hematopoietic cells infiltrating in the myocardium increases mortality and late ventricular remodeling. Our data should encourage performing clinical trials directly targeting NLRP3 inflammasome and their inflammatory cytokines (interleukin-1ß and -18) in MI patients.
RESUMO
We aimed to study the cardiac expression of bone morphogenetic protein 2, its receptor 1 b, and connective tissue growth factor, factors implicated in cardiac embryogenesis, following ischemia/hypoxia, heart failure, and in remodeling hearts from humans and mice. Biopsies from the left ventricle of patients with end-stage heart failure due to dilated cardiomyopathy or coronary artery disease were compared with donor hearts and biopsies from patients with normal heart function undergoing coronary artery bypass grafting. Mouse model of post-infarction remodeling was made by permanent ligation of the left coronary artery. Hearts were analyzed by real-time polymerase chain reaction and Western blotting after 24 hours and after 2 and 4 weeks. Patients with dilated cardiomyopathy and mice post-infarction had increased cardiac expression of connective tissue growth factor. Bone morphogenetic protein 2 was increased in human hearts failing due to coronary artery disease and in mice post-infarction. Gene expression of bone morphogenetic protein receptor 1 beta was reduced in hearts of patients with failure, but increased two weeks following permanent ligation of the left coronary artery in mice. In conclusion, connective tissue growth factor is upregulated in hearts of humans with dilated cardiomyopathy, bone morphogenetic protein 2 is upregulated in remodeling due to myocardial infarction while its receptor 1 b in human failing hearts is downregulated. A potential explanation might be an attempt to engage regenerative processes, which should be addressed by further, mechanistic studies.
Assuntos
Proteína Morfogenética Óssea 2/genética , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/genética , Cardiomiopatia Dilatada/genética , Fator de Crescimento do Tecido Conjuntivo/genética , Doença da Artéria Coronariana/genética , Insuficiência Cardíaca/genética , Adulto , Idoso , Animais , Proteína Morfogenética Óssea 2/metabolismo , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/metabolismo , Cardiomiopatia Dilatada/complicações , Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Dilatada/patologia , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Ponte de Artéria Coronária , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/patologia , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Testes de Função Cardíaca , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Miocárdio/metabolismo , Miocárdio/patologia , Transdução de SinaisRESUMO
Coronary atherosclerosis can lead to myocardial infarction, and secondarily to post-infarct remodelling and heart failure. Retinoic acid (RA) influences cell proliferation. We hypothesized that RA could influence gene expression and proliferation of cardiovascular cells. Left ventricular biopsies from patients with end-stage heart failure due to coronary artery disease (CAD) or dilated cardiomyopathy were investigated for the content of RA metabolites using liquid chromatography mass spectrometry (LC-MS/MS), and compared with healthy donors. All-trans retinoic acid (ATRA) was increased in the hearts of CAD patients. Gene expression (quantitative PCR) of RA target genes was not influenced in failing hearts, but was increased in the hearts of patients with CAD undergoing open heart surgery. The expression of RA target genes was increased in atherosclerotic lesions from carotid arteries compared to healthy arteries. Stimulation of cardiomyocytes, cardiofibroblasts, smooth muscle cells and endothelial cells with ATRA increased the gene expression of the key enzymes. Cardiofibroblast and smooth muscle cell proliferation were reduced by ATRA, which increased endothelial cell proliferation. Coronary artery disease leads to increased expression of RA target genes. ATRA accumulated in the failing human heart. All investigated cell types present in the heart had induced expression of RA target genes when stimulated with ATRA, which also influenced cell proliferation.
Assuntos
Doença da Artéria Coronariana/genética , Infarto do Miocárdio/genética , Receptores do Ácido Retinoico/biossíntese , Tretinoína/administração & dosagem , Biópsia , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/patologia , Fibroblastos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Humanos , Infarto do Miocárdio/patologia , Miocárdio/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Receptores do Ácido Retinoico/genética , Espectrometria de Massas em TandemRESUMO
BACKGROUND: Clinical and experimental studies suggest a pathogenic role for inflammation in chronic heart failure (HF). LIGHT is a member of the tumour necrosis factor superfamily involved in innate and adaptive immune responses. AIMS: We sought to investigate a potential pathogenic role of LIGHT in chronic HF. METHODS: We used various clinical and experimental approaches including studies in post-infarction HF rats and in vitro studies of endothelial cells and peripheral blood mononuclear cells (PBMC). RESULTS: Our main findings were: (i) LIGHT and its receptors (i.e., HVEM and lymphotoxin-beta receptor) were regulated during experimental HF, with strong expression in the infarcted area accompanied by up-regulation of HVEM in cardiomyocytes and endothelial cells also in the non-ischaemic part of the left ventricle. (ii) Patients with chronic HF had significantly increased expression of LIGHT on CD3(+) T-cells accompanied by increased expression of HVEM on monocytes and within the failing myocardium. (iii) LIGHT induced interleukin (IL)-6 expression in endothelial cells. In HF patients, but not in healthy controls, such an IL-6-inducing effect was also seen in LIGHT activated PBMC. CONCLUSION: Our findings in both clinical and experimental HF may suggest a role for LIGHT signalling pathways in the progression of chronic HF involving IL-6-related mechanisms.