The Effect Of Osteoglycin On Hypertension-related Cardiac Fibrosis And Underlying Molecular Mechanism

Rationale: Cardiac fibroblasts play a vital role in the progression of fibrotic cardiac remodeling in hypertensive and failing heart.Osteoglycin(OGN)is implicated as a key regulator of left ventricular mass.However,its precise molecular role in cardiac fibrosis remains unknown.Objective: This study aims to investigate the impact of OGN in hypertensive cardiac remodeling and cardiac fibrosis,as well as underlying molecular mechanism.Methods and Results: Cardiac OGN expression was significantly upregulated in response to both angiotensin Ⅱ(Ang Ⅱ)stimuli and pressure overload induced by transverse aortic constriction(TAC).Absence of OGN resulted in aggravated cardiac interstitial fibrosis and deteriorated cardiac dysfunction in both two rodent models.Furthermore,OGN disruption promotes Ang Ⅱ-induced EGFR activation and cardiac fibroblasts(CFs)proliferation and migration,which was restored by OGN overexpression.OGN overexpression blunted Rho/ROCK-dependent membrane type 1 extracellular matrix metalloproteinase(MMP)translocation to the cell surface,resulted in decreased pro-MMP-2 activation and thereby membrane anchored EGF ligands shedding.Lysophosphatidic acid(LPA)activates Rho/ROCK signaling and regulates cellular motility via specific G protein-coupled receptors.OGN was identified to have a close interaction with LPA3,one of LPA receptor isoforms,to block LPA induced RhoA dependent cytoskeletal remodeling and cellular proliferation and migration.Conclusions: Up-regulation of OGN in response to Ang Ⅱ stimulation inhibits CFs proliferation and migration and protects against hypertensive cardiac interstitial fibrosis.Therefore,targeting OGN is a promising strategy for hypertensive cardiac remodeling.