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

Left ventricular (LV) remodelling after myocardial infarction (MI) is a crucial determinant of the clinical course of heart failure. Matrix metallo-proteinase (MMP) activation is strongly associated with LV remodelling after MI. Elucidation of plasma membrane receptors related to the acti-vation of specific MMPs is fundamental for treating adverse cardiac remodelling after MI. The aim of current investigation was to explore thepotential association between the low-density lipoprotein receptor-related protein 1 (LRP1) and MMP-9 and MMP-2 spatiotemporal expressionafter MI. Real-time PCR and Western blot analyses showed that LRP1 mRNA and protein expression levels, respectively, were significantlyincreased in peri-infarct and infarct zones at 10 and 21 days after MI. Confocal microscopy demonstrated high colocalization between LRP1and the fibroblast marker vimentin, indicating that LRP1 is mostly expressed by cardiac fibroblasts in peri-infarct and infarct areas. LRP1 alsocolocalized with proline-rich tyrosine kinase 2 (pPyk2) and MMP-9 in cardiac fibroblasts in ischaemic areas at 10 and 21 days after MI. Cell cul-ture experiments revealed that hypoxia increases LRP1, pPyk2 protein levels and MMP-9 activity in fibroblasts, without significant changes inMMP-2 activity. MMP-9 activation by hypoxia requires LRP1 and Pyk2 phosphorylation in fibroblasts. Collectively, ourin vivoandin vitrodatasupport a major role of cardiac fibroblast LRP1 levels on MMP-9 up-regulation associated with ventricular remodelling after MIThe research leading to these results received funding from the Instituto de Salud Carlos III (FIS PI14/01729 and FIS PI14/01682) that was cofinanced by the European Fund for Regional Development, as well as from the Ministerio de Ciencia e Innovaci on (SAF2011-30067-C02-01), the Fundacio La Marato de TV3 (201521_10, 201502_30 and 080330), the Red de Terapia Celular-TerCel (RD12/0019/0029), the Red Cardio-vascular (RD12/0042/0027 and RD12/ 0042/0047), the Sociedad Espa~nola de Cardiolog ıa and the Fundaci o Privada Daniel Bravo Andreu. E.R.L. is a recipient of an FI-DGR_B01008 grant from Generalitat de Catalunya, and D.G. is a recipient of CD14/0109 from Sara Borell of the Instituto de Salud Carlos III.Peer reviewe