RESUMO
Collagen crosslinking, mediated by lysyl oxidase, is an adaptive mechanism of the cardiac repair process initiated by cardiac fibroblasts postmyocardial injury. However, excessive crosslinking leads to cardiac wall stiffening, which impairs the contractile properties of the left ventricle and leads to heart failure. In this study, we investigated the role of periostin, a matricellular protein, in the regulation of lysyl oxidase in cardiac fibroblasts in response to angiotensin II and TGFß1. Our results indicated that periostin silencing abolished the angiotensin II and TGFß1-mediated upregulation of lysyl oxidase. Furthermore, the attenuation of periostin expression resulted in a notable reduction in the activity of lysyl oxidase. Downstream of periostin, ERK1/2 MAPK signaling was found to be activated, which in turn transcriptionally upregulates the serum response factor to facilitate the enhanced expression of lysyl oxidase. The periostin-lysyl oxidase association was also positively correlated in an in vivo rat model of myocardial infarction. The expression of periostin and lysyl oxidase was upregulated in the collagen-rich fibrotic scar tissue of the left ventricle. Remarkably, echocardiography data showed a reduction in the left ventricular wall movement, ejection fraction, and fractional shortening, indicative of enhanced stiffening of the cardiac wall. These findings shed light on the mechanistic role of periostin in the collagen crosslinking initiated by activated cardiac fibroblasts. Our findings signify periostin as a possible therapeutic target to reduce excessive collagen crosslinking that contributes to the structural remodeling associated with heart failure.
Assuntos
Moléculas de Adesão Celular , Fibroblastos , Proteína-Lisina 6-Oxidase , Ratos Sprague-Dawley , Animais , Proteína-Lisina 6-Oxidase/metabolismo , Fibroblastos/metabolismo , Ratos , Moléculas de Adesão Celular/metabolismo , Masculino , Sistema de Sinalização das MAP Quinases , Miocárdio/metabolismo , Miocárdio/citologia , Angiotensina II/farmacologia , Angiotensina II/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Células Cultivadas , Modelos Animais de Doenças , PeriostinaRESUMO
The development of novel strategies that aim to augment the regenerative potential of bone is critical for devising better treatment options for bone defects or injuries. Facilitation of bone repair and regeneration utilizing composite hydrogels that simulates bone matrix is emerging as a viable approach in bone tissue engineering. The present study aimed to develop nanohydroxyapatite-incorporated gelatin methacryloyl (GelMA)/poly(ethylene glycol) diacrylate (PEGDA) hydrogel (GMPH hydrogel). A facile blending and photocrosslinking approach was employed to incorporate nanohydroxyapatite into the inter-crosslinked polymeric hydrogel network to obtain an ECM mimicking matrix for assisting bone tissue regeneration. Chemical characterization of GelMA and the GMPH hydrogel was carried out using FTIR and 1H NMR. Physical properties of GMPH, such as gelation, swelling and degradation ratios, and internal morphology, signified the suitability of GMPH hydrogel for tissue engineering. Cell viability assay demonstrated a healthy proliferation of MG63 osteoblast cells in GMPH hydrogel extracted growth medium, indicating the hydrogel's cytocompatibility and suitability for bone tissue engineering. Our study documented the fabrication of a novel GelMA/PEGDA-nanohydroxyapatite hydrogel that possesses ideal physicochemical and biological properties for bone tissue engineering.