Relationship among LRP1 expression, Pyk2 phosphorylation and MMP‐9 activation in left ventricular remodelling after myocardial infarction

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.

Soluble LRP1 is an independent biomarker of epicardial fat volume in patients with type 1 diabetes mellitus

“…The pathological role of sLRP1 in cardiometabolic disease is unclear. Our group has identified the cellular form of LRP1 as a key receptor for cholesterol accumulation in vascular cells 16 – 19 and cardiomyocytes 20 – 22 , and showed that this receptor is strongly upregulated in coronary arteries and myocardium in in vivo models 23 – 25 and patients 22 , 26 – 28 exposed to cardiovascular risk factors. LRP1 has also the potential to interact with different ligands involved in inflammation 29 and coagulation 30 .…”

Developing LRP1 Agonists into a Therapeutic Strategy in Acute Myocardial Infarction

“…LRP1 expression is markedly enhanced during hypoxemia and/or ischemia [51,89,90] under the regulation of the hypoxia-inducible factor-1α (HIF-1α) in cardiomyocytes, as well as in cardiac fibroblasts [89,90,91,92] (Figure 1).…”

“…LRP1 was also strongly up-regulated in the myocardial tissue in the animal models of ischemia-reperfusion [51,90,91], as well as in patients with ischemic cardiomyopathy, supporting a role for LRP1 in IRI [51]. However, the specific role of LRP1 as a scavenger/signaling/scaffold receptor in cardiomyocytes has not been investigated until recently [51,90,92,93].…”

“…Furthermore, various studies have highlighted the role of LRP1 in cardiac remodeling after AMI [92,94]. Enhanced LRP1-mediated cardiomyocyte intracellular CE accumulation up-regulated cathepsin S (CatS), a cysteine protease with the ability to degrade extracellular matrix (ECM) components, and altered structural and physical characteristics of secreted tropoelastin (TE), one of the main components of ECM [94].…”

“…The ERK1/2 expression and phosphorylation were strongly up-regulated in the infarct areas at 1, 10, and 21 days, while the pPky2 expression peaked in the infarct and peri-infarct areas at 10 and 21 days after AMI. The LRP1/pPyk2 axis up-regulated MMP-9 in cardiac fibroblasts, suggesting that LRP1 modulates the fibrotic response that follows the ischemic injury [92]. Taken together, these data allow one to speculate that LRP1 mediates the distinct spatial and temporal activation of ERK1/2- and Pyk2-dependent pathways in cardiomyocytes and fibroblasts, and may explain the differential contribution of these two signaling pathways in the immediate and later phases after AMI [92].…”