RESUMO
Dipeptidyl peptidase-4 (DPP-4) inhibitors are hypoglycemic agents. DPP-4 inhibitor has cardioprotective effects after transverse aortic constriction (TAC), but role of DPP-4 on cardiac fibrosis after TAC is not well known. Our aim was to determine the effects of DPP-4 on cardiac fibrosis in murine TAC model. Wild-type mice and DPP-4 knockout mice were subjected to TAC. Wild-type mice were then treated with vehicle or DPP-4 inhibitor. DPP-4 activities in serum and heart tissue were significantly increased at 2 weeks after TAC, but they were significantly decreased by DPP-4 inhibitor treatment. The inhibition of DPP-4 did not affect left ventricular hypertrophy, but improved cardiac function and decreased myocardial and perivascular fibrosis after TAC. The inhibition of DPP-4 decreased the collagen type III/I ratio in myocardium. These results suggest that DPP-4 inhibition ameliorates the progression of heart failure after TAC by changing the quality and quantity of cardiac fibrosis.
Assuntos
Cardiotônicos , Dipeptidil Peptidase 4/fisiologia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/etiologia , Miocárdio/patologia , Animais , Aorta , Estenose da Valva Aórtica/complicações , Colágeno Tipo I/metabolismo , Colágeno Tipo III/metabolismo , Constrição Patológica , Dipeptidil Peptidase 4/metabolismo , Modelos Animais de Doenças , Fibrose , Insuficiência Cardíaca/patologia , Hipertensão/complicações , Hipertrofia , Masculino , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , PressãoRESUMO
RATIONALE: It is known that the transcriptional coactivator p300 is crucially involved in the differentiation and growth of cardiac myocytes during development. However, the physiological function of p300 in the postnatal hearts remains to be characterized. OBJECTIVE: We have now investigated the physiological function of p300 in adult hearts. METHODS AND RESULTS: We analyzed transgenic mice exhibiting cardiac-specific overexpression of a dominant-negative p300 mutant lacking the C/H3 domain (p300DeltaC/H3 transgenic [TG] mice). p300DeltaC/H3 significantly inhibited p300-induced activation of GATA- and myocyte enhancer factor 2-dependent promoters in cultured ventricular myocytes, and p300DeltaC/H3-TG mice showed cardiac dysfunction that was lethal by 20 weeks of age. The numbers of mitochondria in p300DeltaC/H3-TG myocytes were markedly increased, but the mitochondria were diminished in size. Moreover, cardiac mitochondrial gene expression, mitochondrial membrane potential and ATP contents were all significantly disrupted in p300DeltaC/H3-TG hearts, suggesting that mitochondrial dysfunction contributes to the progression of the observed cardiomyopathy. Transcription of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1alpha, a master regulator of mitochondrial gene expression, and its target genes was significantly downregulated in p300DeltaC/H3-TG mice, and p300DeltaC/H3 directly repressed myocyte enhancer factor 2C-dependent PGC-1alpha promoter activity and disrupted the transcriptional activity of PGC-1alpha in cultured ventricular myocytes. In addition, myocytes showing features of autophagy were observed in p300DeltaC/H3-TG hearts. CONCLUSIONS: Collectively, our findings suggest that p300 is essential for the maintenance of mitochondrial integrity and for myocyte survival in the postnatal left ventricular myocardium.
Assuntos
Potencial da Membrana Mitocondrial , Mitocôndrias Cardíacas/metabolismo , Miócitos Cardíacos/metabolismo , Fatores de Transcrição de p300-CBP/metabolismo , Trifosfato de Adenosina/genética , Trifosfato de Adenosina/metabolismo , Animais , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Sobrevivência Celular/genética , Células Cultivadas , Coração/embriologia , Coração/crescimento & desenvolvimento , Camundongos , Camundongos Transgênicos , Mitocôndrias Cardíacas/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Estrutura Terciária de Proteína/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Ratos , Elementos de Resposta/genética , Transativadores/genética , Transativadores/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcrição Gênica/genética , Fatores de Transcrição de p300-CBP/genéticaRESUMO
Reactivation of the fetal cardiac gene program is a characteristic feature of hypertrophied and failing hearts that correlates with impaired cardiac function and poor prognosis. However, the mechanism governing the reversible expression of fetal cardiac genes remains unresolved. Here we show that neuron-restrictive silencer factor (NRSF), a transcriptional repressor, selectively regulates expression of multiple fetal cardiac genes, including those for atrial natriuretic peptide, brain natriuretic peptide and alpha-skeletal actin, and plays a role in molecular pathways leading to the re-expression of those genes in ventricular myocytes. Moreover, transgenic mice expressing a dominant-negative mutant of NRSF in their hearts exhibit dilated cardiomyopathy, high susceptibility to arrhythmias and sudden death. We demonstrate that genes encoding two ion channels that carry the fetal cardiac currents I(f) and I(Ca,T), which are induced in these mice and are potentially responsible for both the cardiac dysfunction and the arrhythmogenesis, are regulated by NRSF. Our results indicate NRSF to be a key transcriptional regulator of the fetal cardiac gene program and suggest an important role for NRSF in maintaining normal cardiac structure and function.
