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Abstract
Left ventricular (LV) remodelling after myocardial infarction (MI) is a crucial determinant of the clinical course of heart failure. Matrix metalloproteinase (MMP) activation is strongly associated with LV remodelling after MI. Elucidation of plasma membrane receptors related to the activation of specific MMPs is fundamental for treating adverse cardiac remodelling after MI. The aim of current investigation was to explore the potential association between the low‐density lipoprotein receptor‐related protein 1 (LRP1) and MMP‐9 and MMP‐2 spatiotemporal expression after MI. Real‐time PCR and Western blot analyses showed that LRP1 mRNA and protein expression levels, respectively, were significantly increased in peri‐infarct and infarct zones at 10 and 21 days after MI. Confocal microscopy demonstrated high colocalization between LRP1 and the fibroblast marker vimentin, indicating that LRP1 is mostly expressed by cardiac fibroblasts in peri‐infarct and infarct areas. LRP1 also colocalized with proline‐rich tyrosine kinase 2 (pPyk2) and MMP‐9 in cardiac fibroblasts in ischaemic areas at 10 and 21 days after MI. Cell culture experiments revealed that hypoxia increases LRP1, pPyk2 protein levels and MMP‐9 activity in fibroblasts, without significant changes in MMP‐2 activity. MMP‐9 activation by hypoxia requires LRP1 and Pyk2 phosphorylation in fibroblasts. Collectively, our in vivo and in vitro data support a major role of cardiac fibroblast LRP1 levels on MMP‐9 up‐regulation associated with ventricular remodelling after MI.
Highlights
Adverse myocardial remodelling is associated with poor patient outcomes in the setting of ischaemic heart disease and/or myocardial infarction (MI), cardiac hypertrophy and cardiomyopathy disease processes [1,2,3]
Our results indicate that lipoprotein receptor-related protein 1 (LRP1) is a target for modulating cardiac fibroblast Matrix metalloproteinase (MMP)-9 levels during the early stages of fibrosis after MI
We demonstrated that LRP1 levels are extremely high in cardiac fibroblasts during the fibrotic states of remodelling after MI
Summary
Adverse myocardial remodelling is associated with poor patient outcomes in the setting of ischaemic heart disease and/or MI, cardiac hypertrophy and cardiomyopathy disease processes [1,2,3]. Adverse cardiac remodelling after MI causes ventricular functional impairment and heart failure (HF). The incidence of HF after MI is determined by infarct area size, infarct wound healing and chronic LV remodelling [4,5,6]. Cardiomyocyte apoptosis and necrosis involving infarcted regions and residual viable myocardium trigger a cascade of immune-inflammatory pathways and cellular mechanisms that promote wound a 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine
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