Osteoglycin Prevents Cardiac Dilatation and Dysfunction After Myocardial Infarction Through Infarct Collagen Strengthening
Rationale: To maintain cardiac mechanical and structural integrity after an ischemic insult, profound alterations occur within the extracellular matrix. Osteoglycin (OGN) is a small leucine-rich proteoglycan previously described as a marker of cardiac hypertrophy.
Objective: To establish whether OGN may play a role in cardiac integrity and function after myocardial infarction (MI).
Methods and Results: OGN expression is associated with collagen deposition and scar formation in mouse and human MI. Absence of OGN in mice resulted in significantly increased rupture-related mortality with tissue disruption, intramyocardial bleeding and increased cardiac dysfunction, despite equal infarct sizes. Surviving OGN null mice had greater infarct expansion in comparison to WT mice due to impaired collagen fibrillogenesis and maturation in the infarcts as revealed by electron microscopy and collagen polarization. Absence of OGN did not affect cardiomyocyte hypertrophy in the remodeling remote myocardium. In cultured fibroblasts, OGN knockdown or supplementation did not alter TGF-ß signaling. Adenoviral overexpression of OGN in WT mice significantly improved collagen quality, thereby blunting cardiac dilatation and dysfunction following MI. In OGN null mice, adenoviral overexpression of OGN was unable to prevent rupture-related mortality due to insufficiently restoring OGN protein levels in the heart. Finally, circulating OGN levels in heart failure patients were significantly increased in the patients with a previous history of myocardial infarction compared to those with non-ischemic heart failure and correlated with survival, left ventricular volumes and other markers of fibrosis.
Conclusions: Increased OGN expression in the infarct scar promotes proper collagen maturation and protects against cardiac disruption and adverse remodeling following MI. In human heart failure, OGN is a promising biomarker for ischemic heart failure.
- Received June 12, 2014.
- Revision received December 14, 2014.
- Accepted December 17, 2014.