Abstract 415: Asporin Contributes to Reactive Interstitial Cardiac Fibrosis by Regulating Cardiac Fibroblast Activation

Abstract

Cardiac fibrosis critically contributes to heart failure progression. Depending on the pathological insult, cardiac fibrosis either replaces necrotic cardiomyocytes or is reactive to cardiac fibroblast (CF) activation. The extracellular matrix (ECM) consists of various proteins and the role of fibrillar collagen has been well studied. However, the role of non-fibrillar ECM proteins in cardiac fibrosis is less clear. To explore the role of ECM in reactive cardiac fibrosis, we performed bioinformatic analysis on online available microarray GEO datasets from hearts of human hypertrophic cardiomyopathy patients and two mouse models of transverse aortic constriction and Angiotensin II (AngII) infusion. We found that 27 differentially expressed genes were common between the three datasets. Among these genes was the small leucine-rich proteoglycan Asporin (ASPN). ASPN was previously shown to be upregulated in the ECM of replacement fibrosis in porcine ischemia/reperfusion injury. However, not much is known about the role of ASPN in reactive interstitial fibrosis. We show that cardiac ASPN expression is enhanced in mice after short- and long-term AngII infusion compared to saline infusion. In resident CF isolated from adult mice, ASPN expression is upregulated by both AngII and TGF-β stimulation. Here, ASPN expression correlates with a gene signature of activated CFs including periostin ( postn ), α-smooth muscle actin ( acta2 ) and collagens I and III ( col1a1, col3a1 ), and with functional characteristics of activated CFs including proliferation, migration and collagen production. Modulating ASPN via siRNA in mouse resident CFs inhibits postn, acta2, col1a1 and col3a1 expression and total collagen production, indicating repressed CF activation upon ASPN knockdown. Taken together, ASPN may be an attractive novel target against reactive interstitial fibrosis.