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Relationship among LRP1 expression, Pyk2 phosphorylation and MMP-9 activation in left ventricular remodelling after
Elena Revuelta-López1,2, Carol Soler-Botija2, Laura Nasarre1
1Cardiovascular Research Center, CSIC-ICCC, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
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.
Insights
Low-density lipoprotein receptor-related protein 1 (LRP1) is upregulated in cardiac fibroblasts after myocardial infarction (MI), promoting matrix metalloproteinase-9 (MMP-9) activation and contributing to adverse ventricular remodelling.
Area of Science:
- Cardiovascular Biology
- Cardiac Remodeling
- Matrix Metalloproteinases
Background:
- Left ventricular (LV) remodeling post-myocardial infarction (MI) significantly impacts heart failure progression.
- Matrix metalloproteinase (MMP) activation is a key factor in adverse cardiac remodeling after MI.
- Identifying plasma membrane receptors involved in MMP activation is crucial for therapeutic development.
Purpose of the Study:
- To investigate the association between low-density lipoprotein receptor-related protein 1 (LRP1) and the expression of MMP-9 and MMP-2 after MI.
- To determine the cellular localization and functional role of LRP1 in cardiac fibroblasts following ischemic injury.
Main Methods:
- Quantitative real-time PCR and Western blot analysis to assess LRP1, MMP-9, and MMP-2 expression.
- Confocal microscopy to evaluate colocalization of LRP1 with cardiac fibroblast and signaling markers.
- In vitro cell culture experiments under hypoxic conditions to study LRP1, pPyk2, and MMP activity.
Main Results:
- LRP1 mRNA and protein levels were significantly elevated in infarct and peri-infarct zones at 10 and 21 days post-MI.
- LRP1 predominantly localized to cardiac fibroblasts expressing vimentin in ischemic areas.
- LRP1 colocalized with pPyk2 and MMP-9 in fibroblasts; hypoxia increased LRP1, pPyk2, and MMP-9 activity, dependent on LRP1 and Pyk2 phosphorylation.
Conclusions:
- Cardiac fibroblast LRP1 plays a critical role in upregulating MMP-9 activity following myocardial infarction.
- LRP1-mediated MMP-9 activation in fibroblasts contributes to pathological ventricular remodeling after MI.
- Targeting LRP1 in cardiac fibroblasts may offer a therapeutic strategy to mitigate adverse cardiac remodeling.