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Int J Mol Sci ; 18(11)2017 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-29088068

RESUMO

Cardiac remodeling plays a crucial role in the development of heart failure after mycocardial infarction. Besides cardiomyocytes, endothelial cells are recognized to contribute to cardiac remodeling. We now investigated processes of endothelial mesenchymal transition (EndoMT) in microvascular endothelial cells of rat (MVEC) under hypoxia and paracrine effects on ventricular cardiomyocytes of adult rat. Exposure of MVECs to hypoxia/reoxygenation enhanced TGFß/SMAD signaling, since phosphorylation, and thus activation, of SMAD1/5 and SMAD2 increased. This increase was blocked by inhibitors of TGFß receptor types ALK1 or ALK5. Exposure of ventricular cardiomyocytes to conditioned medium from hypoxic/reoxygenated MVECs enhanced SMAD2 phosphorylation and provoked apoptosis in cardiomyoyctes. Both were blocked by ALK5 inhibition. To analyze autocrine effects of hypoxic TGFß signaling we investigated EndoMT in MVECs. After 3 days of hypoxia the mesenchymal marker protein α-smooth muscle actin (α-SMA), and the number of α-SMA- and fibroblast specific protein 1 (FSP1)-positive cells increased in MVECs cultures. This was blocked by ALK5 inhibition. Similarly, TGFß1 provoked enhanced expression of α-SMA and FSP1 in MVECs. In conclusion, hypoxia provokes EndoMT in MVECs via TGFß1/SMAD2 signaling. Furthermore, release of TGFß1 from MVECs acts in a paracrine loop on cardiomyocytes and provokes apoptotic death. Thus, in myocardial infarction hypoxic endothelial cells may contribute to cardiac remodeling and heart failure progression by promotion of cardiac fibrosis and cardiomyocytes death.


Assuntos
Apoptose , Células Endoteliais/metabolismo , Miócitos Cardíacos/metabolismo , Oxigênio/metabolismo , Transdução de Sinais , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Actinas/metabolismo , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Hipóxia Celular , Células Cultivadas , Células Endoteliais/citologia , Endotélio Vascular/citologia , Masculino , Microvasos/citologia , Miócitos Cardíacos/citologia , Comunicação Parácrina , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Ratos Wistar , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Receptores de Fatores de Crescimento Transformadores beta/metabolismo
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