SPARC production by bone marrow-derived cells contributes to myocardial fibrosis in pressure overload

Abstract

Myocardial fibrosis and the resultant increases in LV and myocardial stiffness represent pivotal consequences of chronic pressure overload (PO). In this study, a murine model of cardiac fibrosis induced by PO was used to demonstrate a critical function of SPARC in bone marrow-derived cells that drives cardiac fibrosis and increases in cardiac macrophages.

Phenotypic characterization of primary cardiac fibroblasts from patients with HFpEF

“…However, the changes in fibroblast phenotype do not explain the increases in procollagen processing and collagen content that occur after prolonged LVPO. In the murine model, we reported one determinant of increased collagen deposition was dependent upon increases in myocardial macrophages recruited in response to PO which would not be represented in the in vitro fibroblast system reported here [14].…”

The Role of Matrix Proteins in Cardiac Pathology

“…Alters fibrotic gene programming in cardiac fibroblasts [88,89] -Regulates macrophages, regulatory T cells and leukocytes -Regulates proliferation and migration of cardiac stromal cells -Mediates post-synthetic collagen processing and interaction with cardiac fibroblasts -Alters expression of ECM and adhesion molecule genes in fibroblasts -Activates TGF-β signaling pathway [97][98][99][100][101]104,[111][112][113]184] Tenascin C (TN-C) Syndecan-1: -Inhibits leukocyte adhesion and migration -Downregulates monocyte chemoattractant protein-1 expression -Regulates MMP-2 and -9 activity -Regulates Smad2 phosphorylation Syndecan-4: -Regulates cardiac fibroblast signaling, adhesion, migration and differentiation -Regulates cardiomyocyte apoptosis -Alters caspase3 and phospho-ERK expression, along with NFAT signaling -Regulates collagen production in cardiac fibroblasts [173][174][175][176][177][178][181][182][183] Abbreviations: ANGII: angiotensin II; ERK: extracellular signal-regulated kinase; LV: left ventricle; LVH: left ventricular hypertrophy; MI: myocardial infarction; MMPs: matrix metalloproteinases; NFAT: nuclear factor of activated T cells; PAI-1: plasminogen activator inhibitor 1; PAH: pulmonary arterial hypertension RV: right ventricle; SPARC: secreted protein that is acidic and rich in cysteine; TAC: transverse aortic constriction; TN-C: tenascin-C; TSP: thrombospondin; WT: wild-type.…”

“…Myocardial macrophages have been identified as a source of SPARC in the pressureoverloaded myocardium [112,113]. An increase in macrophage-derived SPARC and total collagen production is detected from one week in TAC-treated hearts, followed by an increase in insoluble collagen production and associated increase in myocardial stiffness at two weeks [112].…”

“…An increase in macrophage-derived SPARC and total collagen production is detected from one week in TAC-treated hearts, followed by an increase in insoluble collagen production and associated increase in myocardial stiffness at two weeks [112]. A recent study highlighted the importance of bone marrow-derived SPARC in the fibrotic response [113]. SPARC-null mice transplanted with wild-type bone marrow and subjected to LV pressure overload produced a similar fibrotic response to that of wild-type mice, and had a greater infiltration of cardiac macrophages when compared to wild-type mice transplanted with SPARC-null bone marrow.…”

Titanium Nanoparticles Enhance Production and Suppress Stabilin-1-Mediated Clearance of GDF-15 in Human Primary Macrophages

“…Quantitative confocal microscopy analysis further confirmed the abrogation of stabilin-1 expression in M2 co-cultured with TiNPs. A decrease in stabilin-1 can also result in impaired clearance of SPARC, modified lipoproteins and apoptotic bodies, the accumulation of which is frequent in chronic inflammation and fibrosis ( 53 , 55 , 56 , 58 ). Moreover, deficiency of stabilin-1 in mice aggravates inflammation by increased inflammatory macrophage activation and enhanced IgM production ( 59 ).…”