Biglycan Is Required for Adaptive Remodeling After Myocardial Infarction

Abstract

Background-After myocardial infarction (MI), extensive remodeling of extracellular matrix contributes to scar formation and preservation of hemodynamic function. On the other hand, adverse and excessive extracellular matrix remodeling leads to fibrosis and impaired function. The present study investigates the role of the small leucine-rich proteoglycan biglycan during cardiac extracellular matrix remodeling and cardiac hemodynamics after MI. Methods and Results-Experimental MI was induced in wild-type (WT) and bgn Ϫ/0 mice by permanent ligation of the left anterior descending coronary artery. Biglycan expression was strongly increased at 3, 7, and 14 days after MI in WT mice. bgn Ϫ/0 mice showed increased mortality rates after MI as a result of frequent left ventricular (LV) ruptures. Furthermore, tensile strength of the LV derived from bgn Ϫ/0 mice 21 days after MI was reduced as measured ex vivo. Collagen matrix organization was severely impaired in bgn Ϫ/0 mice, as shown by birefringence analysis of Sirius red staining and electron microscopy of collagen fibrils. At 21 days after MI, LV hemodynamic parameters were assessed by pressure-volume measurements in vivo to obtain LV end-diastolic pressure, end-diastolic volume, and end-systolic volume. bgn Ϫ/0 mice were characterized by aggravated LV dilation evidenced by increased LV end-diastolic volume (bgn

Deficiency of Biglycan Causes Cardiac Fibroblasts to Differentiate into a Myofibroblast Phenotype

“…The changes in the TGF-␤ system were paralleled by induction of PLOD1, PLOD2 and MMP13 in bgn Ϫ/0 fibroblasts, which is in line with the myofibroblastic phenotype and suggests that bgn Ϫ/0 fibroblasts showed differences with respect to matrix remodeling. These results are also in line with the increased expression of MMP13 in bgn Ϫ/0 hearts in vivo after MI as described earlier (22). During the first 48 h post-MI, macrophages infiltrate the infarcted area and secrete cytokines and growth factors, such as TGF-␤, leading to the appearance of myofibroblasts (12).…”

“…Furthermore genetic deletion of both SLRPs caused a distinct cardiac phenotype after experimental MI, characterized by disturbed remodeling and hemodynamic insufficiency (21,22). These experiments revealed a more severe phenotype in bgn Ϫ/0 compared with decorin Ϫ/Ϫ mice, as evidenced by rupture of infarct scars and increased mortality in bgn Ϫ/0 mice.…”

“…To numb the throat and reduce gag reflex a drop of 1% lidocaine was put on the tip of the tube. Mice were subjected to permanent LADocclusion followed by recovery for 3 or 7 days as described before (22). Infarcted left ventricles were used for immunoblotting and total RNA was isolated from the apex.…”

“…Furthermore, bgn is a ligand of CD44 (19), a cell surface receptor that is postulated to functionally interact with TGF-␤ in myofibroblast differentiation (20). With respect to cardiac pathophysiology, it is known that both SLRPs, biglycan, and decorin, are up-regulated during infarct healing (21,22). Bgndeficient male mice (bgn Ϫ/0 ) experience increased mortality and impaired hemodynamic function after experimental MI and a higher incidence of ventricular ruptures.…”

“…Bgndeficient male mice (bgn Ϫ/0 ) experience increased mortality and impaired hemodynamic function after experimental MI and a higher incidence of ventricular ruptures. The underlying mechanism appears to be a distorted and fragile collagen scar in the absence of biglycan (22,23). As myofibroblasts are the main players in establishing of the infarct scar the aim of this study was to elucidate the role of biglycan for phenotypic control of cardiac fibroblasts.…”